| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Treatment of participants with RCC in the adjuvant setting |
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| E.1.1.1 | Medical condition in easily understood language |
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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 | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10038395 |
| E.1.2 | Term | Renal carcinoma |
| E.1.2 | System Organ Class | 100000004864 |
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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 |
To compare disease-free survival (DFS) as assessed by the investigator for participants treated with pembrolizumab versus those receiving placebo
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| E.2.2 | Secondary objectives of the trial |
1. To compare overall survival (OS) for participants treated with pembrolizumab versus those receiving placebo
2. To compare the safety and tolerability profiles for participants treated with pembrolizumab versus those receiving placebo
3. To compare measures of disease recurrence-specific survival (DRSS), as assessed by the investigator, in participants treated with pembrolizumab versus those receiving placebo
4. To compare DFS and OS according to participants’ PD-L1 expression status (Positive, Negative) for participants treated with pembrolizumab versus those receiving placebo
5. To evaluate pharmacokinetic (PK) parameters and the presence of antidrug antibodies (ADA)
6. To evaluate patient-reported outcomes (PROs) with the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC-QLQ- C30) and the Functional Assessment of Cancer Therapy Kidney Symptom Index – Disease Related Symptoms (FKSI-DRS) |
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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 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.Must have histologically confirmed diagnosis of RCC with clear cell component with or without sarcomatoid features. Diagnosis of RCC with clear cell component is to be made by the investigator and does not require central histology review
2.Be ≥ 18 years of age on day of signing informed consent
3.Female participants of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to randomization. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
4.Female participants of childbearing potential must be willing to use an adequate method of contraception as outlined in the protocol, for the course of the trial through 120 days after the last dose of trial drug
5.Male participants of childbearing potential must be willing to use an adequate method of contraception as outlined in the protocol, for the course of the trial through 120 days after the last dose of trial drug
6.The participant provides written informed consent/assent for the trial. The participant may also provide consent/assent for Future Biomedical Research; however the participant may participate in the main trial without participating in Future Biomedical Research
7.Have intermediate-high risk, high risk, or M1 NED RCC as defined by the following pathological tumor-node-metastasis and Fuhrman grading status:
a)Intermediate-high risk RCC
-pT2, Gr. 4 or sarcomatoid, N0, M0
-pT3, Any Gr., N0, M0
b)High risk RCC
- pT4, Any Gr. N0, M0
-pT Any stage, Any Gr., N+, M0
c)M1 NED RCC -participants who present not only with the primary kidney tumor but also solid, isolated, soft tissue metastases that can be completely resected at one of the following:
- the time of nephrectomy (synchronous) or,
- ≤1 year from nephrectomy (metachronous)
8.Have received no prior systemic therapy for advanced RCC
9.Have undergone a partial nephroprotective or radical complete nephrectomy (and complete resection of solid, isolated, soft tissue metastatic lesion(s) in M1 NED participants) with negative surgical margins
10.Must have undergone a nephrectomy and/or metastasectomy ≥28 days prior to signing informed consent and ≤12 weeks prior to randomization.
11.Must be tumor-free as assessed by the Investigator and validated by either CT or MRI scan of the brain and CAP and a bone scan ≤28 days from randomization. All baseline scans must be sent to the central imaging vendor and receipt must be confirmed prior to randomization
12.Must have provided adequate tissue per the following:
- Nephrectomy only: tissue from nephrectomy (required).
- Synchronous M1 NED: tissue from nephrectomy (required) AND, metastasectomy issue (if available).
- Metachronous M1 NED: tissue from metastasectomy (required) AND, nephrectomy tissue (if available).
Adequacy of the samples for biomarker analysis will be evaluated by a central laboratory.
13.Have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1
14.Have adequate organ function as defined in the protocol. Specimens must be collected within 10 days prior to randomization |
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| E.4 | Principal exclusion criteria |
1.Has had major surgery, other than nephrectomy and/or resection of pre-existing metastases for M1 NED participants, within 12 weeks prior to randomization
2.Has received prior radiotherapy for RCC
3. Has pre-existing brain or bone metastatic lesions.
4.Has residual thrombus post nephrectomy in the vena renalis or vena cava
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 the first dose of study treatment
6.Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, 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) is not considered a form of systemic treatment and is allowed
7.Has a known additional malignancy that is progressing or required active treatment ≤3 years ago. Exceptions include early-stage cancers (carcinoma in situ or Stage 1) treated with curative intent, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, in situ cervical cancer, in situ prostate cancer, or in situ breast cancer that has undergone potentially curative therapy
8.Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
9.Has an active infection requiring systemic therapy
10. Has a history of, or is currently on, dialysis
11.Has a known history of human immunodeficiency virus infection. No human immunodeficiency virus testing is required unless mandated by local health authority
12.Has a known active hepatitis B (hepatitis B surface antigen reactive) or hepatitis C virus (eg, hepatitis C virus [HCV] RNA [qualitative] is detected)
13.Has a known history of active tuberculosis (Bacillus tuberculosis)
14.Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the participant’s participation for the full duration of the trial, or is not in the best interest of the participant to participate, in the opinion of the treating investigator
15.Has a known psychiatric or substance abuse disorder that would interfere with the cooperation with the requirements of the trial in the opinion of the investigator
16.Has had a prior solid organ transplant
17.Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients
18.A woman of childbearing potential (WOCBP) who has a positive urine pregnancy test within 72 hours before randomization. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Participants must be excluded/discontinued from the trial in the event of a positive or borderline positive test result
19.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 study treatment
20.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 (ie, CTLA-4, OX-40, CD137) or has previously participated in a Merck pembrolizumab (MK 3475) clinical trial
21.Has received prior anticancer therapy, monoclonal antibody, chemotherapy, or an investigational agent or device within 4 weeks or 5 half-lives (whichever is longer) before first dose of study treatment or not recovered (ie, must be ≤Grade 1 or at baseline) from AEs due to previously administered agents
22.Has received a live vaccine within 30 days prior to the first dose of study treatment. 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, 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
23.Is currently participating in or has participated in a trial of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Disease-free survival (DFS) as assessed by the investigator |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Every 12 weeks from randomization through follow-up year 1, every 16 weeks during follow-up year 2 to year 4 and every 24 weeks during year 5 and beyond until disease recurrence Survival status may be requested during the course of the study to ensure data is current and complete at any data base locks (interim/final). |
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| E.5.2 | Secondary end point(s) |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| every 12 weeks after disease recurrence. Survival status may be requested during the course of the study to ensure data is current and complete at any data base locks (interim/final). |
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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 | No |
| 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 | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 74 |
| 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 |
| Australia |
| Brazil |
| Canada |
| Chile |
| China |
| Colombia |
| Japan |
| Korea, Republic of |
| New Zealand |
| Russian Federation |
| Taiwan |
| United States |
| Finland |
| France |
| Germany |
| Ireland |
| Italy |
| Netherlands |
| Poland |
| Spain |
| United Kingdom |
| Czechia |
| Argentina |
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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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| 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 | 6 |
| 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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