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.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
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) |
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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 |
Part 1 (Safety Run-In):
Objective: To evaluate the safety and tolerability of 3 pembrolizumab + chemotherapy combinations, namely, pembrolizumab + paclitaxel, pembrolizumab + nab paclitaxel, and pembrolizumab + gemcitabine/carboplatin.
Part 2 (Phase III study):
Objective: To compare progression-free survival (PFS) based on Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by a blinded central imaging vendor (CIV) in all subjects.
Objective: To compare PFS based on RECIST 1.1 as assessed by a blinded CIV in subjects with programmed cell death ligand 1 (PD-L1) positive tumors.
Objective: To compare overall survival (OS) in all subjects.
Objective: To compare OS in subjects with PD-L1 positive tumors.
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E.2.2 | Secondary objectives of the trial |
Objective: To compare objective response rate (ORR) based on RECIST 1.1 as assessed by a blinded CIV in all subjects.
Objective: To compare ORR based on RECIST 1.1 as assessed by a blinded CIV in subjects with PD-L1 positive tumors.
Objective: To evaluate duration of response (DOR) based on RECIST 1.1 as assessed by a blinded CIV in all subjects and in subjects with PD L1 positive tumors.
Objective: To compare disease control rate (DCR) based on RECIST 1.1 as assessed by a blinded CIV in all subjects and in subjects with PD-L1 positive tumors.
Objective: To evaluate the safety and tolerability of 3 pembrolizumab + chemotherapy combinations. |
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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 and tumor tissue) 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 |
1.Have locally recurrent inoperable breast cancer not previously treated with chemotherapy and which cannot be treated with curative intent.
OR
Have metastatic breast cancer not previously treated with chemotherapy.
Note: Subjects with a history of locally recurrent breast cancer, which was previously treated with curative intent, may be eligible.
2.Have centrally confirmed TNBC, as defined by the most recent ASCO/CAP guidelines.
Note: Subjects initially diagnosed with hormone receptor–positive and/or HER2 positive breast cancer must have central confirmation of TNBC in a tumor biopsy obtained from a local recurrence or distant metastasis site.
3.Have completed treatment for Stage I-III breast cancer, if indicated, and ≥6 months elapsed between the completion of treatment with curative intent (e.g., date of primary breast tumor surgery or date of last adjuvant chemotherapy administration, whichever occurred last) and first documented local or distant disease recurrence.
Note: First documentation of local or distant disease recurrence must be in the form of a dated biopsy, pathology, or imaging study report. A laboratory report indicating tumor marker elevation cannot be used as documentation of local or distant disease recurrence, unless accompanied by dated biopsy, pathology, or imaging study report.
Note: Subjects who received taxane, gemcitabine, or platinum agents in the (neo)adjuvant setting can be treated with same class of chemotherapy (taxane or gemcitabine/carboplatin), if ≥12 months have elapsed between the completion of treatment with curative intent (e.g., date of primary breast tumor surgery or date of last adjuvant chemotherapy administration, whichever occurred last) and first documented local or distant disease recurrence.
4.Have been treated with (neo)adjuvant anthracycline, if they received systemic treatment in the (neo)adjuvant setting, unless anthracycline was contraindicated or not considered the best treatment option for the subject in the opinion of the treating physician.
Note: Subjects presenting with de novo metastatic TNBC are eligible for the study, if anthracycline is contraindicated or not considered the best treatment option for the subject in the opinion of the treating physician.
5.Have measurable disease based on RECIST 1.1 as determined by local radiology review.
Note: Target lesions situated in a previously irradiated area are considered measurable, only if they have shown unequivocal progression based on RECIST 1.1 after radiation therapy.
Note: Chest wall recurrence can be used as a target lesion, only if measurable by diagnostic quality imaging modality (digital photography alone is not adequate).
6.Have provided recently or newly obtained core or excisional biopsy from a locally recurrent inoperable or metastatic tumor lesion for central determination of TNBC status and PD-L1 expression, unless contraindicated due to site inaccessibility and/or subject safety concerns.
Note: Adequacy of biopsy specimen for the above analyses must be confirmed by the central laboratory. Submission of another tumor specimen may be required, if adequate tumor tissue was not provided the first time.
Note: An archival tumor specimen obtained before the diagnosis of locally recurrent inoperable or metastatic breast cancer may be submitted after consultation with the Sponsor, if neither a recently nor a newly obtained biopsy from a locally recurrent inoperable or a metastatic site is available.
7.Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, as assessed within 10 days prior to the start of study treatment.
8.Have life expectancy ≥12 weeks from randomization.
9.Demonstrate adequate organ function, within 10 days prior to the start of study treatment, as defined in the following table.
Refer to protocol for complete list.
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E.4 | Principal exclusion criteria |
1.Is currently participating in a clinical study and receiving an investigational agent and/or using an investigational device, or has participated in a clinical study and received an investigational agent and/or used an investigational device within 4 weeks prior to randomization.
Note: Subjects who have entered the follow-up phase of a clinical 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 not recovered (e.g., to ≤Grade 1 or to baseline) from AEs due to a previously administered therapy.
Note: Alopecia of any grade is an exception to this criterion.
Note: Prior to randomization, the subject must have recovered adequately from any toxicity and/or complications associated with any recent procedure.
3.Has neuropathy ≥Grade 2.
4.Has an active autoimmune disease that has required systemic treatment in the past 2 years (e.g., 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) is not considered a form of systemic treatment.
5.Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to randomization.
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, and in situ cervical cancer.
7.Has known active CNS metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they have stable brain metastases and did not receive chemotherapy for metastatic breast cancer.
Note: Known brain metastases are considered active, if any of the following criteria are 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.
Radiographic stability of previously treated brain metastases is based on local radiology/investigator review, but dated reports of 2 imaging studies (the most recent performed during screening) documenting stability of brain metastasis(es) over ≥4 weeks must be submitted to the Sponsor. Such brain imaging studies should be available at the site for submission to CIV, if later needed.
b.Neurological symptoms attributed to brain metastases have not returned to baseline
c.Steroids were used for management of symptoms related to brain metastases within 28 days of randomization
8.Has active, or a history of, pneumonitis requiring treatment with steroids.
9.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 (such as CTLA-4, OX 40, CD137) or has previously participated in Merck pembrolizumab (MK-3475) clinical studies.
Refer to protocol for compete list.
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E.5 End points |
E.5.1 | Primary end point(s) |
Overall Survival (OS) and Progression Free Survival (PFS) were selected as the co-primary endpoints. OS has been recognized as the gold standard for demonstration of superiority for new anti neoplastic therapies, whereas PFS based on RECIST 1.1 has been an acceptable endpoint and has been used as a primary efficacy endpoint in a number of randomized Phase III studies in metastatic breast cancer |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Post-baseline imaging assessments should be performed at 8, 16, and 24 weeks post randomization, and then every 9 weeks during the first year. After 1 year, subjects who remain on treatment will have imaging performed every 12 weeks. Imaging should continue to be performed until disease progression is verified by CIV (unless the investigator further follows irRECIST and continues study treatment until PD confirmation at least 4 weeks later), the start of new anti cancer treatment, withdrawal of consent, death, or end of the study, whichever occurs first.
In the Survival Follow-Up phase, a subject should be contacted by telephone every 12 weeks (or more often as needed) to assess for survival status until death, withdrawal of consent, or the end of the study, whichever occurs first.
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E.5.2 | Secondary end point(s) |
1.Objective Response Rate (ORR) – based on RECIST 1.1 as assessed by a CIV
Objective response rate is defined as the proportion of the subjects in the analysis population who have a CR or PR. Responses are based on assessments by a CIV per RECIST 1.1.
2.Duration of Overall Response (DOR) – based on RECIST 1.1 as assessed by a CIV
For subjects who demonstrate CR or PR, duration of response is defined as the time from first documented evidence of CR or PR until disease progression or death due to any cause, whichever occurs first, based on assessments by a CIV per RECIST 1.1. See Section 8.6.1 – Statistical Methods for Efficacy Analyses for the definition of censoring.
3.Disease Control Rate (DCR) – based on RECIST 1.1 as assessed by a CIV
Disease control rate is defined as the percentage of subjects who have achieved CR or PR or have demonstrated SD for at least 24 weeks, based on assessments by a CIV per RECIST 1.1.
4.Safety and Tolerability |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Post-baseline imaging assessments should be performed at 8 weeks, 16 weeks, and 24 weeks post randomization, and then every 9 weeks during the first year. After 1 year, subjects who remain on treatment will have imaging performed every 12 weeks. Imaging timing should follow calendar days and should not be adjusted for delays in cycle starts.
Safety will be evaluated from the time the subject signs Informed Consent through as long as 90 days following the cessation of all study therapy. |
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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 | Yes |
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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
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 | Yes |
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
| 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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 60 |
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 |
Austria |
Belgium |
Brazil |
Canada |
Chile |
Colombia |
Czech Republic |
Denmark |
Finland |
France |
Germany |
Hong Kong |
Italy |
Japan |
Korea, Republic of |
Malaysia |
Mexico |
Netherlands |
New Zealand |
Poland |
Russian Federation |
Spain |
Taiwan |
Turkey |
United Kingdom |
United States |
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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
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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 | 5 |
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 | 5 |
E.8.9.2 | In all countries concerned by the trial days | 0 |