| Eligibility |
Inclusion Criteria:
1. Male/female participants who are at least 18 years of age on the day of signing
informed consent with histologically confirmed diagnosis of clear cell renal cell
carcinoma will be enrolled in this study.
2. Have undergone a partial nephrectomy or radical complete nephrectomy with negative
surgical margins.
3. Evidence of oligo-metastatic disease eligible for local treatment with radiotherapy or
surgery, defined as:
1. Appearance of new metastases within 5 years from previous eradication of primary
tumors or previous metastasectomy.
2. Presence of maximum 3 metastases in the same site or in different sites with the
exception of bone metastases that cannot exceed the number of 2 if they are the
sole disease site or one in case of multiple sites.
3. Each metastasis should be less than 3 cm in the maximum diameter and less than 5
cm in the sum of the longest tumor diameters (this evaluation should apply also
for lymph nodes).
4. Has received no prior systemic therapy for Renal Cell Carcinoma (RCC).
5. Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 within 7
days of before the start of study intervention.
6. The participant (or legally acceptable representative) has provided documented
informed consent/assent for the study.
7. Have provided archival tumor tissue sample or newly obtained core or excisional biopsy
of a primary tumor or tumor lesion not previously irradiated. Formalin-fixed, paraffin
embedded (FFPE) tissue blocks are preferred to slide. Newly obtained biopsies are
preferred to archived tissue.
Female participants:
8. A female participant is eligible to participate if she is not pregnant, not
breastfeeding, and at least one of the following conditions applies:
1. Not a woman of childbearing potential (WOCBP) as defined in Appendix 3 of the
Study protocol OR
2. A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the
treatment period and for at least 120 days (corresponding to time needed to
eliminate any study treatment(s)) plus 30 days (a menstruation cycle) for study
treatments with risk of genotoxicity after the last dose of study treatment.
9. Adequate organ function defined as:
System - Laboratory Value
Hematological
- Absolute neutrophil count (ANC): = 1500/µl
- Platelets: = 100 000/µl
- Hemoglobin: = 9.0 g/dL or = 5.6 mmol/L
Renal
- Creatinine: =1.5 x Upper Limit of Normal (ULN) OR
- Measured or calculated creatinine clearance: = 30 mL/min for participant with
creatinine levels > 1.5 x institutional ULN (GFR can also be used in place of
creatinine or CrCl)
Hepatic
- Total bilirubin: = 1.5 x ULN OR direct bilirubin = ULN for participants with total
bilirubin levels > 1.5 x ULN
- Aspartate transaminase (AST or SGOT) and alanine transaminase (ALT or SGPT): = 2.5 x
ULN (= 5 ULN for participants with liver metastases)
Coagulation
- International normalized ratio (INR) OR prothrombin time (PT)
- Activated partial thromboplastin time (aPTT): = 1.5 x ULN unless participant is
receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of
intended use of anticoagulants
Exclusion Criteria:
1. Has had major surgery, other than nephrectomy, within 4 weeks prior to randomization.
Note: If participants received major surgery, they must have recovered adequately from
the toxicity and/or complications from the intervention prior to starting study
treatment.
2. Has residual thrombus post nephrectomy in the vena renalis or vena cava.
3. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with
an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4,
OX-40, CD137).
4. Has received prior systemic anti-cancer therapy including investigational agents
within 4 weeks prior to randomization.
Note: Participants must have recovered from all Adverse Events (AEs) due to previous
therapies to =Grade 1 or baseline. Participants with =Grade 2 neuropathy may be
eligible. Participants with endocrine-related AEs Grade =2 requiring treatment or
hormone replacement may be eligible
5. Has clinically significant cardiovascular disease within 12 months from first dose of
study intervention, including NYHA Class III or IV congestive heart failure, unstable
angina, myocardial infarction, cerebral vascular accident, undergone CABG or PTCA, or
cardiac arrhythmia.
Note: Medically controlled arrhythmia stable on medication is permitted.
6. Has moderate to severe hepatic impairment (Child-Pugh B or C).
7. Has received prior radiotherapy within 2 weeks of start of study intervention.
Participants must have recovered from all radiation-related toxicities, not require
corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted
for palliative radiation (=2 weeks of radiotherapy) to non-central nervous system
(CNS) disease.
8. Has received a live vaccine or live-attenuated vaccine within 30 days prior to the
first dose of study drug. Administration of killed vaccines is allowed.
9. Is currently participating in or has participated in a study of an investigational
agent or has used an investigational device within 4 weeks prior to the first dose of
study intervention.
Note: Participants who have entered the follow-up phase of an investigational study
may participate as long as it has been 4 weeks after the last dose of the previous
investigational agent.
10. 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 to the first dose of study drug.
11. Has a known additional malignancy that is progressing or has required active treatment
within the past 3 years. Participants with basal cell carcinoma of the skin, squamous
cell carcinoma of the skin, non-muscle invasive bladder cancer, prostate cancer pT2 or
less, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have
undergone potentially curative therapy are not excluded.
12. Has known active CNS metastases and/or carcinomatous meningitis. Participants with
previously surgically treated brain metastases may participate provided they are not
radiological evidence of disease at the time of screening and without evidence of
progression for at least 12 months by repeat imaging (note that the repeat imaging
should be performed during study screening).
13. Has severe hypersensitivity (=Grade 3) to pembrolizumab and/or any of its excipients.
14. Has active autoimmune disease that has required systemic treatment in the 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 and is allowed.
15. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required
steroids or has current pneumonitis/interstitial lung disease.
16. Has an active infection requiring systemic therapy.
17. Has a known history of Human Immunodeficiency Virus (HIV) infection.
18. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg]
reactive) or known active Hepatitis C virus (HCV, defined as HCV RNA is detected)
infection. Note: no testing for Hepatitis B and Hepatitis C is required unless
mandated by local health authority.
19. Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the study, interfere with the participant's
participation for the full duration of the study, or is not in the best interest of
the participant to participate, in the opinion of the treating investigator.
20. Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
21. Is pregnant or breastfeeding or expecting to conceive or father children within the
projected duration of the study, starting with the screening visit through 120 days
after the last dose of trial treatment.
22. Has had an allogenic tissue/solid organ transplant.
23. A WOCBP who has a positive urine 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.
Note: in the event that 72 hours have elapsed between the screening pregnancy test and the
first dose of study treatment, another pregnancy test (urine or serum) must be performed
and must be negative in order for subject to start receiving study medication.
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