Study of Lenvatinib Plus Pembrolizumab in IO Refractory mRCC Patients With Brain Metastases

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 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.