| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic Triple Negative Breast Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Metastatic Triple Negative 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 | 10075566 |
| E.1.2 | Term | Triple negative 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 |
PD-L1 Positive Populations: subjects with PD-L1 positive expression defined by ≥10 Combined Positive Score (CPS) and by ≥1 CPS; henceforth abbreviated as CPS ≥10 and CPS ≥1 respectively.
(1) To compare OS in subjects with PD-L1 positive tumors (CPS ≥10).
(2) To compare OS in subjects with PD-L1 positive tumors (CPS ≥1).
(3) To compare OS in all subjects. |
|
| E.2.2 | Secondary objectives of the trial |
(1) To compare progression-free survival (PFS) based on RECIST 1.1 as assessed by blinded central imaging vendor in all subjects.
(2) To compare overall response rate (ORR) per RECIST 1.1 by blinded central imaging vendor in all subjects.
(3) To evaluate PFS and ORR based on RECIST 1.1 as assessed by blinded central imaging vendor in subjects with PD-L1 positive tumors (CPS ≥10 and CPS ≥1).
(4) To evaluate duration of response (DOR), and disease control rate (DCR) based on RECIST 1.1 as assessed by blinded central imaging vendor in subjects with PD-L1 positive tumors (CPS ≥10 and CPS ≥1) and in all subjects.
(5) To determine the safety and tolerability of pembrolizumab. |
|
| 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 |
| Merck will conduct Future Biomedical Research on DNA (blood) specimens collected during this clinical trial. Such research is for biomarker testing to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding of diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose of the correct drug at the correct time. |
|
| E.3 | Principal inclusion criteria |
1.Have received either one or two prior systemic treatments for metastatic breast cancer and have documented disease progression on or after their most recent therapy.
2.Have been previously treated with an anthracycline and/or taxane in the (neo)adjuvant or metastatic setting.
3.Have centrally confirmed mTNBC (determined by a newly obtained core or excisional biopsy from a metastatic, not previously irradiated, tumor lesion).
4.Have measurable disease based on RECIST 1.1 as assessed by site Investigator and local radiology review.
5.Have provided a newly obtained core or excisional biopsy from a metastatic, not previously irradiated, tumor lesion for central determination of triple-negative breast cancer status and PD-L1 biomarker analysis. Adequacy of the biopsy specimen for the above analyses must be confirmed by the central laboratory. Repeat samples may be required if adequate tumor tissue is not provided.
Note: Subjects for whom fresh tumor biopsies cannot be obtained (eg inaccessible tumor site or concern for subject safety) may submit an archived tumor specimen only upon agreement from the Sponsor.
6.Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 assessed within 10 days prior of treatment initiation. |
|
| E.4 | Principal exclusion criteria |
1.Has participated or is currently participating in a study of an investigational agent/device and has received/is receiving the investigational agent/device within 4 weeks of randomization.
Note: A subjects who has entered the follow-up phase of an investigational study may participate as long as 4 weeks have elapsed since the last dose of the investigational agent and/or removal of the device.
2.Has had monoclonal antibody (mAb) for direct anti-neoplastic treatment within 4 weeks of randomization
3.Has had chemotherapy, targeted small molecule therapy, or radiation therapy within at least 2 weeks of randomization
4.Has not recovered from adverse events (ie, downgraded to ≤ Grade 1 or to baseline) from adverse events due to a previously administered therapy.
Note: Subjects with ≤ Grade 2 neuropathy or alopecia of any grade are an exception to this criterion and may qualify for the study.
Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the surgery prior to randomization.
5.Has an active autoimmune disease that has required systemic treatment in the past 2 years (ie with use of disease modifying agents, corticosteroids or immunosuppressive drugs).
Note: Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
6.Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days of randomization.
7.Has a known additional malignancy that progressed or required active treatment within the last 5 years. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy, and in situ cervical cancer.
cancer.
8. Has known active brain metastases and/or carcinomatous meningitis. Note: Known brain metastases are considered active, if any of the following criteria is applicable: a. Brain imaging during screening demonstrates progression of existing metastases and/or appearance of new lesions compared to brain imaging performed at least 4 weeks earlier. b. Neurological symptoms attributed to brain metastases have not returned to baseline. c. Steroids were used for brain metastases within 28 days of randomization
9. Has active/history of pneumonitis requiring treatment with steroids or active/history of interstitial lung disease.
10.Has an active infection requiring systemic therapy.
11.Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating Investigator.
12.Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
13.Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment.
14.Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another co-inhibitory T-cell receptor (eg CTLA-4, OX-40, CD137) or has previously participated in Merck MK-3475 clinical trials.
15.Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
16.Has a known active Hepatitis B (eg, hepatitis B surface antigen [HBsAg] reactive) or Hepatitis C (eg, hepatitis C virus [HCV] RNA [qualitative] is detected).
Has received a live vaccine within 30 days of randomization
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Overall survival (OS) in subjects with CPS ≥10
2. OS in subjects with CPS ≥1
3. OS in all subjects |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
•Interim Analysis
Timing: approximately 14 mo after enrollment is completed. It is estimated that ~ 130, 284 and 445 OS events will be accrued in sbj with CPS ≥10, CPS ≥1 and all subjects.
Purpose: interim efficacy analysis for OS
•Final analysis
- Triggered by duration of follow-up and OS events in subjects with CPS ≥1: ~ 24 mo after enrollment is completed or 334 OS events accrue in sbj with CPS ≥1, whichever occurs later. ~ 154, 334 and 520 OS events
will be accrued in sbj with CPS ≥10, CPS ≥1 and all sbj.
- If OS events in sbj with CPS ≥1 accrue slower than expected and fewer than 334 events are observed 26 mo after enrolment is completed, then the Sponsor will conduct the final analysis at that time Purpose: final efficacy analysis for OS |
|
| E.5.2 | Secondary end point(s) |
-PFS based on RECIST 1.1 by blinded central imaging vendor in all subjects
-ORR based on RECIST 1.1 by blinded central imaging vendor in all subjects
-PFS based on RECIST 1.1 by blinded central imaging vendor in subjects with CPS ≥10 and subjects with CPS ≥1
-ORR based on RECIST 1.1 by blinded central imaging vendor in subjects with CPS ≥10 and subjects with CPS ≥1
-DCR based on RECIST 1.1 by blinded central imaging vendor in subjects with CPS ≥10, subjects with CPS ≥1 and all subjects
-DOR based on RECIST 1.1 by blinded central imaging vendor in subjects with CPS ≥10, subjects with CPS ≥1 and all subjects |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Analysis of the secondary endpoints will be provided at IA-efficacy. |
|
| 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 | No |
| 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) | 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 | 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 43 |
| 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 |
| Australia |
| Brazil |
| Colombia |
| Guatemala |
| Hong Kong |
| Japan |
| Korea, Republic of |
| Malaysia |
| Mexico |
| New Zealand |
| Peru |
| Philippines |
| Russian Federation |
| Singapore |
| South Africa |
| Taiwan |
| Thailand |
| Turkey |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
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