Inclusion Criteria:
1. Male/female participants .18 years of age on the day of signing informed consent
withhistologically confirmed diagnosis of RCC, irrespective of histologic will be
enrolled in this study. Because no dosing or adverse event data are currently
available on the use of lenvatinib in combination with pembrolizumab in patients <18
years of age, children are excluded from this study.
2. Criteria for brain metastasis:
1. Has at least 1 measurable brain metastasis with no prior history of SRT:
Presence of at least 1 independently verified, non-irradiated, measurable brain
metastasis, defined as at least 5 mm AND twice the MRI slice thickness, but
less than or equal to 3 cm, that can be accurately assessed at baseline and
suitable for accurate repeated measurements.
2. Has at least 1 measurable brain metastasis with prior history of SRT to other
brain metastases: A history of SRT for brain metastases is allowed up to 1 week
before study treatment provided that neurologic sequelae are resolved. If the
patient will be enrolled to the study immediately after SRS it is encouraged to
have 1-5 measurable untreated measurable lesion(s) remain, defined as at least
5 mm AND twice the MRI slice thickness, but less than or equal to 3 cm.
3. Has no measurable brain metastasis with prior SRT: A history of immediate prior
SRT for brain metastases is allowed up to 1 week before study treatment
provided that neurologic sequelae are resolved.
4. If the patient had prior SRT, progression in irradiated lesion must have
occurred at least 1 month after the end of radiation therapy for the irradiated
lesion to be counted as measurable.
5. Patients can have asymptomatic (no neurologic signs or symptoms, not requiring
immediate local intervention [surgery or radiosurgery] or systemic >10 mg
prednisone or equivalent per day glucocorticoid therapy [within 10 days prior
to study treatment initiation]) OR minimally symptomatic brain metastases
(requiring .10 mg prednisone or equivalent per day and not requiring immediate
surgical or radiation therapy in the opinion of the treating investigator and a
radiation therapy or neurosurgical consultant).
3. Patients with brain metastasis that have not received prior systemic therapy may be
eligible to enroll in this study.
4. Male participants: A male participant must agree to use a contraception as detailed
in Appendix 10 of this protocol during the treatment period and for at least 120
days after the last dose of study treatment and refrain from donating sperm during
this period.
5. Female participants: A female participant is eligible to participate if she is not
pregnant (see Appendix 10), not breastfeeding, and at least one of the following
conditions applies:
1. Not a woman of childbearing potential (WOCBP) as defined in Appendix 10 OR. 2. A WOCBP who agrees to follow the contraceptive guidance in Appendix 10 during
the treatment period and for at least 120 days after the last dose of study
treatment.
6. Participants must have progressed on any prior line of treatment with an
anti-PD-1/L1 mAb administered either as monotherapy or in combination with other
checkpoint inhibitors or other therapies. PD-1 treatment progression is defined by
meeting all of the following criteria:
1. Has received at least 2 doses of an approved anti-PD-1/L1 mAb.
2. Has demonstrated disease progression after anti-PD-1/L1 as defined by RECIST
v1.1. The initial evidence of PD is to be confirmed by a second assessment no
less than 4 weeks from the date of the first documented disease progression, in
the absence of rapid clinical progression.
3. Any number of prior treatments including anti-PD-1/L1 mAb are allowed.
Anti-PD-1/L1 mAb does not have to be the most recent therapy.
7. Participants who have AEs due to previous anticancer therapies must have recovered
to .Grade 1 or baseline. Participants with endocrine-related AEs who are adequately
treated with hormone replacement or participants who have .Grade 2 neuropathy are
eligible.
8. The participant has ability to understand and the willingness to sign a written
informed consent.
9. Extracranial disease is not required and if present, it can be measurable or
non-measurable (RECIST v1.1-Appendix 2).
10. Archival tumor tissue sample or newly obtained [core, incisional or excisional]
biopsy of a tumor lesion not previously irradiated has been provided. FFPE tissue
blocks are preferred to slides.
Newly obtained biopsies are preferred to archived tissue.
11. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
(Appendix 4). Evaluation of ECOG is to be performed within 7 days prior to the first
dose of study intervention.
12. Has a life expectancy .12 weeks.
13. Have adequately controlled blood pressure (BP) with or without antihypertensive
medications, defined as BP .150/90 mm Hg with no change in antihypertensive
medications within 1 week prior to study treatment.
14. Criteria for known Hepatitis B and C positive subjects. Hepatitis B and C screening tests are not required unless:
- - Known history of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.
- - As mandated by local health authority.
Hepatitis B positive subjects. . Participants who are HBsAg positive are eligible if they have received HBV
antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to
randomization. . Participants should remain on anti-viral therapy throughout study
intervention and follow local guidelines for HBV anti-viral therapy post completion
of study intervention.
Participants with history of HCV infection are eligible if HCV viral load is
undetectable at screening.
• Participants must have completed curative anti-viral therapy at least 4 weeks
prior to study enrollment.
15. Have adequate organ function as defined in the following table (Table 1). Specimens
must be collected within 10 days prior to the start of study intervention.
Table 1 Adequate Organ Function Laboratory Values System Laboratory Value Hematological
Absolute neutrophil count (ANC) .1500/ƒÊL Platelets .100 000/ƒÊL Hemoglobin .9.0 g/dL or
.5.6 mmol/La Renal Creatinine OR .1.5 ~ ULN OR Measured or calculatedb creatinine
clearance (GFR can also be used in place of creatinine or CrCl)
- - 30 mL/min for participant with creatinine levels >1.5 ~ institutional ULN Hepatic
Total bilirubin .
1.5 ~ULN OR direct bilirubin .ULN for participants with total
bilirubin levels >1.5 ~ ULN AST (SGOT) and ALT (SGPT) .2.5 ~ ULN (.5 ~ ULN for
participants with liver metastases) Coagulation International normalized ratio (INR)
OR prothrombin time (PT) Activated partial thromboplastin time (aPTT)
- - 1.5 ~ ULN unless participant is receiving anticoagulant therapy as long as PT or
aPTT is within therapeutic range of intended use of anticoagulants a Criteria must
be met without erythropoietin dependency and without packed red blood cell (pRBC)
transfusion within last 2 weeks.
b Creatinine clearance (CrCl) should be calculated
per institutional standard. Note: This table includes eligibility-defining
laboratory value requirements for treatment; laboratory value requirements should be
adapted according to local regulations and guidelines for the administration of
specific chemotherapies.
Exclusion Criteria:
1. Has symptomatic brain metastasis requiring immediate procedure (surgery, radiation
treatment), or corticosteroids in dosing exceeding 10 mg daily of prednisone
equivalent.
2. Has received whole brain radiation treatment previously. 3. Has overt hemorrhagic brain metastasis. 4. Has received prior therapy with lenvatinib. 5. Has clinical or radiographic evidence of leptomeningeal disease. 6. Has had major surgery within 3 weeks prior to first dose of study interventions.
Note: Adequate wound healing after major surgery must be assessed clinically,
independent of time elapsed for eligibility. Patients must have adequately recovered
from major surgery and has no ongoing surgical complications.
7. Has prior history of .Grade 3 toxicity attributed to immune checkpoint inhibitor
treatment.
8. Has severe hypersensitivity (.Grade 3) to pembrolizumab and/or any of its
excipients.
9. Patients must have recovered from all radiation-related toxicities, not require
corticosteroids in dosing exceeding 10 mg daily of prednisone equivalent, and not
have had radiation pneumonitis.
10. Active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks prior
to the first dose of study drug.
11. Has a history of (non-infectious, non-radiation-induced) pneumonitis not responsive
to steroids or has current pneumonitis/interstitial lung disease. Patients will also
be excluded if there are respiratory issues including active infection or require
supplemental oxygen for activities of daily living.
12. Has preexisting .Grade 3 gastrointestinal or non-gastrointestinal fistula.
13. Gastrointestinal malabsorption or any other condition that might affect the
absorption of lenvatinib. 14. Has urine protein .1 g/24 hours. Note: Participants with proteinuria .2+ (.100
mg/dL) on urine dipstick testing (urinalysis) will undergo 24-hour urine collection
for quantitative assessment of proteinuria.
15. Has a left ventricular ejection fraction (LVEF) below or equal to the institutional
(or local laboratory) normal range, as determined by multigated acquisition (MUGA)
or echocardiogram (ECHO).
16. Prolongation of the corrected QT interval by Fridericia formula (QTcF) interval to
>480 ms.
17. Has clinically significant cardiovascular disease within 12 months from first dose
of study intervention, including New York Heart Association Class III or IV
congestive heart failure, unstable angina, myocardial infarction, cerebral vascular
accident, or cardiac arrhythmia associated with hemodynamic instability (Appendix
11). Note: Medically controlled arrhythmia would be permitted.
18. Contraindications to MRI (implanted metal device or foreign bodies) or MRI contrast
(insufficient renal function or allergy).
19. Has a condition requiring systemic treatment with either corticosteroids (>10 mg
daily) prednisone equivalent.
20. Has active autoimmune disease that has required systemic treatment in the past 3
months or a documented history of clinical severe autoimmune disease, or a syndrome
that requires chronic systemic steroids or immunosuppressive agents. Replacement
therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy
for adrenal or pituitary insufficiency with prednisone < 10 mg or the equivalent,
etc.) is not considered a form of systemic treatment. Subjects with thyroid disease
or vitiligo will not be excluded from the study.
21. Has an active infection requiring systemic therapy.
22. Has a known history of human immunodeficiency virus.
23. Has a known history of HBV (defined as hepatitis B surface antigen reactive) or
known active HCV (defined as hepatitis C virus RNA [qualitative] is detected)
infection.
24. Unable to swallow and retain oral medications.
25. A WOCBP who has a positive urine pregnancy test within 72 hours prior to allocation
(Appendix 10). If the urine test is positive or cannot be confirmed as negative, a
serum pregnancy test will be required.
26. 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.
27. Has received prior systemic anti-cancer therapy including investigational agents
within 2 weeks or 5 half-lives, whichever is shorter, prior to study treatment
initiation.
28. Has received a live vaccine or live-attenuated vaccine within 30 days before the
first dose of study intervention. Administration of killed vaccines is allowed.
29. 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.
30. Known additional malignancy that is progressing or has required active treatment
within the past 2 years except for except for in situ carcinoma of any site,
adequately treated (without recurrence post-resection or post- radiotherapy)
carcinoma of the cervix or basal or squamous cell carcinomas of the skin, or active
non-threatening second malignancy that would not, in the investigator's opinion,
potentially interfere with the patient's ability to participate and/or complete this
trial. Examples include but not limited to urothelial cancer grade Ta or T1,
adenocarcinoma of the prostate treated by active surveillance.
31. Has a history or current evidence of any condition, therapy, or laboratory
abnormality or other circumstance that might confound the results of the study,
interfere with the participant's participation for the full duration of the study,
such that it is not in the best interest of the participant to participate, in the
opinion of the treating investigator.
32. Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
33. Has had an allogenic tissue/solid organ transplant.
34. Has bleeding or thrombotic disorder(s) or uses anticoagulants such as warfarin or
similar agents requiring therapeutic INR monitoring. Treatment with low molecular
weight heparin is allowed.
