| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Triple-Negative Breast Cancer |
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| E.1.1.1 | Medical condition in easily understood language |
| Triple-Negative Breast Cancer |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 |
Objective (Cohorts A+C): To evaluate the Overall Response Rate (ORR) to pembrolizumab as 2L+ monotherapy in subjects with PD-L1 strong (+) centrally confirmed mTNBC, based on RECIST 1.1 as assessed by the central imaging vendor.
Objective (Cohort A): To evaluate the ORR to pembrolizumab as 2L+ monotherapy for PD-L1 (+) centrally confirmed mTNBC, based on RECIST 1.1 as assessed by the central imaging vendor.
Objective (Cohort A): To evaluate the ORR to pembrolizumab as 2L+ monotherapy for centrally confirmed mTNBC independent of PD-L1 status (all comers), based on RECIST 1.1 as assessed by the central imaging vendor.
Objective (Cohorts A-C): To determine the safety and tolerability of pembrolizumab monotherapy for mTNBC across cohorts and by PD-L1 status within the line of treatment for mTNBC.
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| E.2.2 | Secondary objectives of the trial |
Objective: To estimate the Duration of Response (DOR) to pembrolizumab as 2L+ monotherapy for PD-L1 strong (+) mTNBC* (Cohorts A+C), PD-L1 (+) mTNBC* (Cohort A), and mTNBC* independent of PD-L1 status (Cohort A), based on RECIST 1.1.
Objective: To estimate the Disease Control Rate (DCR), Progression-Free Survival (PFS) and Overall Survival (OS) in patients receiving pembrolizumab as 2L+ monotherapy for PD-L1 strong (+) mTNBC* (Cohorts A+C), PD-L1 (+) mTNBC* (Cohort A), and mTNBC* independent of PD-L1 status (Cohort A), based on RECIST 1.1.
Objective (Cohort B): To estimate the antitumor efficacy (as measured by ORR, DOR, DCR, PFS, and OS) of pembrolizumab as 1L monotherapy for PD-L1 (+) mTNBC*.
Objective (Cohort A): To explore the association between PD-L1 protein expression by IHC and antitumor efficacy of pembrolizumab in 2L+ monotherapy mTNBC based on RECIST 1.1.
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| 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. |
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| E.3 | Principal inclusion criteria |
For Cohorts A and C (2L+ monotherapy), potential subjects must:
1. Have received at least one systemic treatment for metastatic breast cancer and have documented disease progression on the most recent therapy. Subjects must have been previously treated with an anthracycline and a taxane in the (neo)adjuvant or metastatic setting.
Note for Cohort A: In the event that the interim analysis shows that pembrolizumab monotherapy is futile in subjects with PD-L1 (-) mTNBC, subsequent enrollment to Cohort A may be limited to subjects with PD-L1 (+) tumors. If this is the case, sites will be notified via a Protocol Clarification Letter.
For Cohort B (1L monotherapy), potential subjects must:
2. Have not received prior systemic anti-cancer therapy for mTNBC, and
3. Have PD-L1 (+) mTNBC.
For the purposes of this study, neoadjuvant and/or adjuvant chemotherapy regimens do not count as a prior line of therapy.
For Cohort C (2L+ monotherapy), potential subjects must:
4. Have PD-L1 strong (+) mTNBC, i.e. subject’s tumor must meet or exceed the PD-L1 cut point for high positivity.
For all cohorts, potential subjects must:
5. Be willing and able to provide written informed consent/assent for the trial. The subject may also provide consent/assent for Future Biomedical Research. However, the subject may participate in the main trial without participating in Future Biomedical Research.
6. Be ≥ 18 years of age on day of signing informed consent.
7. Be a female or male subject with mTNBC. Central determination of triple-negative breast cancer status is required for enrollment.
8. Have provided tumor tissue for PD-L1 biomarker analysis from a newly obtained core or excisional biopsy of a metastatic tumor lesion not previously irradiated (mandatory). Adequacy of the biopsy specimen for PD-L1 biomarker analysis must be confirmed by the central analysis laboratory. Repeat samples may be required if adequate tissue is not provided.
a. Note: Subjects for whom tumor biopsies cannot be freshly obtained (e.g. inaccessible tumor or subject safety concern) may submit an archived metastatic tumor specimen only upon agreement from the sponsor.
b. Note: If emerging data demonstrates that there is no difference in the clinical utility of PD-L1 assessment in newly obtained samples relative to archived ones, then archived samples may be acceptable without Sponsor agreement. If this is the case, sites will be notified via an Administrative Memo.
9. Have measurable metastatic disease based on RECIST 1.1 as determined by the central imaging vendor. Tumor lesions situated in a previously irradiated area are considered measurable, if progression has been demonstrated in such lesions.
a. Note: The same imaging modality, acquisition and technical parameters should be used throughout the study for tumor imaging.
10. Have a performance status of 0 or 1 on the ECOG Performance Scale. Assessment should be performed within 10 days of treatment initiation.
11. Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication (Reference Section 5.7.2). Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year.
Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy.
Abstinence is acceptable if this is the established and preferred contraception for the subject.
12. Demonstrate adequate organ function.
13. Female subjects of childbearing potential should 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 cannot be confirmed as negative, a serum pregnancy test will be required.
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| E.4 | Principal exclusion criteria |
1. Is currently participating and receiving study therapy, or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.
Note: Subjects who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks since the last dose of the previous investigational agent or device.
2. Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
3. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
4. Has had a prior anti-cancer monoclonal antibody (mAb) for direct anti-neoplastic treatment within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
5. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within at least 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.
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 intervention prior to starting therapy.
6. 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, or in situ cervical cancer.
7. Has radiographically detectable (even if asymptomatic and/or previously treated) central nervous system (CNS) metastases and/or carcinomatous meningitis. Brain imaging at screening is required.
8. Has history of pneumonitis requiring treatment with steroids or history of interstitial lung disease.
9. Has an active infection requiring systemic therapy.
10. 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.
11. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
12. 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.
13. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2 agent or with an agent directed to another co-inhibitory T-cell receptor (e.g. CTLA-4, OX-40, CD137) or has participated in Merck MK-3475 trials.
14. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
15. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
16. Has received a live vaccine within 30 days of planned start of study therapy.
Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.
17. Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or child) who is investigational site or sponsor staff directly involved with this trial, unless prospective IRB approval (by chair or designee) is given allowing exception to this criterion for a specific subject.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy objective of this study is to evaluate the anti-tumor activity of pembrolizumab in subjects with TNBC. Response rates per RECIST 1.1as assessed by the central vendor will be used as the primary response rate efficacy endpoint. Overall response rate will also be used as the primary endpoint due to the single-arm design of this study.
RECIST 1.1 will also be used by the local site for treatment decisions. However RECIST 1.1 will be adapted to account for the unique tumor response profile seen with immunotherapies such as pembrolizumab. Immunotherapeutic agents such as pembrolizumab may produce antitumor effects by potentiating endogenous cancer-specific immune responses which may be functionally anergic. The response patterns seen with such an approach may extend beyond the typical time course of responses seen with cytotoxic agents, and can manifest a clinical response after an initial increase in tumor burden or even the appearance of new lesions. Standard RECIST criteria may not provide a complete response assessment of immunotherapeutic agents such as pembrolizumab. Therefore, RECIST 1.1 will be used with the following adaptation, outlined in Section 7.1.2.7.3.2 of the protocol, termed irRECIST.
When feasible, subjects should not be discontinued until progression is confirmed. This allowance to continue treatment despite initial radiologic progression takes into account the observation that some subjects can have a transient tumor flare in the first few months after the start of immunotherapy, but with subsequent disease response.
The primary safety objective of this trial is to characterize the safety and tolerability of pembrolizumab in subjects with TNBC. The primary safety analysis will be based on subjects who experienced toxicities as defined by CTCAE criteria. Safety will be assessed by quantifying the toxicities and grades experienced by subjects who have received pembrolizumab, including serious adverse events (SAEs) and events of clinical interest (ECIs).
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Safety and Response will be assessed throughout the entire study. Response assessments are scheduled for every 9 weeks for the first year, with additional assessments following at 12 week intervals. |
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| E.5.2 | Secondary end point(s) |
| A secondary objective of this trial is the evaluation of the relationship between PD-L1 biomarker status as assessed by immunohistochemistry and response to pembrolizumab. The data obtained in this trial with regard to the biomarker will inform the performance of PD-L1 assessment by IHC, and may determine if the definition of PD-L1 positivity should be modified for future trials or specific populations. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| A fresh tumor sample is required at screening. |
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| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 18 |
| 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 |
| Belgium |
| Brazil |
| Canada |
| Colombia |
| France |
| Germany |
| Israel |
| Italy |
| Japan |
| Mexico |
| New Zealand |
| Puerto Rico |
| Russian Federation |
| Singapore |
| South Africa |
| Spain |
| Turkey |
| United Kingdom |
| United States |
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| 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
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| The overall trial ends when the last subject completes the last study-related phone-call or trial visit, discontinues from the trial or is lost to follow-up (i.e. the subject is unable to be contacted by the investigator). |
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| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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