| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Triple-Negative Breast Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| 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 |
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):
1. 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.
2. To compare PFS based on RECIST 1.1 as assessed by a blinded CIV in
subjects with PD-L1 positive tumors (combined positive score [CPS] ≥1).
3. To compare PFS based on RECIST 1.1 as assessed by a blinded CIV in
subjects with PD-L1 positive tumors (CPS ≥10).
4. To compare overall survival (OS) in all subjects.
5. To compare OS in subjects with PD-L1 positive tumors (CPS ≥1).
6. To compare OS in subjects with PD-L1 positive tumors (CPS ≥10). |
|
| E.2.2 | Secondary objectives of the trial |
Part 2 (Phase III study):
1. To compare objective response rate (ORR) based on RECIST 1.1 as assessed by a blinded CIV in all subjects, in subjects with PD-L1 positive tumors (CPS ≥1 and CPS ≥10).
2. 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 (CPS ≥1 and CPS ≥10).
3. To compare DCR based on RECIST 1.1 as assessed by a blinded CIV in
ll subjects and in subjects with PD-L1 positive tumors (CPS ≥1 and CPS ≥10).
4. To evaluate the safety and tolerability of 3 pembrolizumab + chemotherapy combinations.
5. To evaluate changes in health-related quality-of-life (QoL) assessments from baseline in all subjects and in subjects with PD-L1 positive tumors (CPS ≥1 and CPS ≥10) using the European Organization
for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and EORTC Breast Cancer– Specific Quality of Life Questionnaire (EORTC QLQ-BR23). |
|
| 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. |
|
| 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: Adjuvant radiation therapy is not considered treatment with curative intent for the purpose of calculating the ≥6 month interval requirement described above.
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.
10. A female participant is eligible to participate if she is not pregnant or breastfeeding,and at least one of the following conditions applies:
• Is not a WOCBP
OR
Is a WOCBP and:
- Uses a contraceptive method that is highly effective.
- Has a negative highly-sensitive pregnancy test.
- Has had her medical history, menstrual history, and recent sexual activity reviewed by the investigator to decrease the risk for inclusion of a woman with an early undetected pregnancy.
11. Male participants are eligible to participate if they agree to:
-Refrain from donating sperm
PLUS either:
• Be abstinent from heterosexual intercourse as their preferred and usual lifestyle.
OR
• Must agree to use contraception unless confirmed to be azoospermic. |
|
| 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.
Note: Subjects who were treated with radiation therapy may participate as long as at least 2 weeks have elapsed since the last dose of radiation therapy was administered.
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 known brain metastases may participate provided that the brain metastases have been previously treated (except with chemotherapy) and are radiographically stable. To demonstrate radiographic stability of previously treated brain metastases, a minimum of 2 post-treatment brain imaging assessments are required: 1) The first brain imaging must be acquired after treatment of brain metastases has been completed 2) The second brain imaging must be obtained during screening (i.e. within 28 days of randomization) and ≥ 4 weeks after the previous post-treatment brain imaging.
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 history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
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.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Part 1:
Safety and tolerability.
Part 2:
1. 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.
2. PFS based on RECIST 1.1 as assessed by a blinded CIV in subjects
with PD-L1 positive tumors (CPS ≥1).
3. PFS based on RECIST 1.1 as assessed by a blinded CIV in subjects
with PD-L1 positive tumors (CPS ≥10).
4. Overall survival (OS) in all subjects.
5. OS in subjects with PD-L1 positive tumors (CPS ≥1).
6. OS in subjects with PD-L1 positive tumors (CPS ≥10). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
One safety interim analysis for Part 1 and 3 efficacy interim analyses for Part 2 will be performed.
Part 1
Safety IA: ~ 3 mo after first subject randomized.
After all Part 1 subjects have completed the first 21 or 28 days (depending on chemotherapy treatment) of treatment.
Part 2
IA1- interim PFS and interim OS analysis: ~ 9 months after first 640 Part 2 subjects are randomized.
IA2 - interim OS analysis and final PFS analysis. After ~ 185 OS events among subjects with CPS ≥10 have been observed.
IA3 - interim OS analysis: after ~ 210 OS events among subjects with CPS ≥10 have been observed.
FA - final OS analysis: after ~ 664 OS events among all subjects, ~ 482 OS events among subjects with CPS ≥1, and ~ 240 OS events among subjects with CPS ≥10 have been observed. |
|
| E.5.2 | Secondary end point(s) |
Part 2
Objective response rate (ORR) based on RECIST 1.1 as assessed by a blinded CIV in all subjects and in subjects with PD-L1 positive tumors (CPS ≥1). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Interim analysis 1 (IA1): ~ 9 months after first 640 Part 2 subjects are randomized.
Primary purpose: final ORR analysis. |
|
| 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 | 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 | 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Part 1: open-label study. Part 2: double-blind, part under in-house blinding procedures. |
|
| 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 | 3 |
| 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 |
| Brazil |
| Canada |
| Chile |
| Colombia |
| Hong Kong |
| Japan |
| Korea, Republic of |
| Malaysia |
| Mexico |
| New Zealand |
| Taiwan |
| United States |
| Russian Federation |
| Turkey |
| Austria |
| Belgium |
| Czechia |
| Denmark |
| Finland |
| France |
| Germany |
| Italy |
| Netherlands |
| Poland |
| Spain |
| United Kingdom |
|
| 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 | 5 |
| 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 | 5 |
| 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 |
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