ABEMA Alone or in COMBO With MK-6482

Inclusion Criteria

• Histologically or cytologically confirmed unresectable advanced or metastatic renal cell carcinoma with clear cell component. Patients with extensive sarcomatoid histology are accepted.
• Participants must have failed or developed an intolerance to at least 1 prior anti-VEGFR systemic therapy and 1 immune checkpoint inhibitor for metastatic RCC. No limit on the number of prior lines of therapies.
• Measurable disease as per RECIST 1.1. See section 12 for the evaluation of measurable disease.
• Age ≥ 18 years
• ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A)
• Participants must undergo fresh tumor biopsy unless medically unsafe or not feasible.
• Normal organ and marrow function as defined below:
• Absolute neutrophil count ≥1,500/mcL
• Platelets ≥100,000/mcL
• Hemoglobin ≥10g/dL (transfusions allowed)
• Total bilirubin ≤2.0 x institutional upper limit of normal with the following exception: patients with known Gilbert disease should have a serum bilirubin ≤ 3 x ULN
• AST(SGOT)/ALT(SGPT)≤3.0 × institutional upper limit of normal with the following exception: patients with known liver metastases should have AST and ALT

≤ 5 x ULN

• Creatinine clearance ≥30 mL/min/1.73 m2 according to the Cockcroft-Gault equation. (APPENDIX F)
• Urine protein/creatinine ratio (UPC ratio) ≤2
• Women of child-bearing potential and men must agree to use adequate contraception (intrauterine device or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation and 6 months after completion abemaciclib plus MK- 6482 and at least 3 weeks after the completion of abemaciclib administration. If condoms are used as a barrier method, a spermicidal agent should be added as a double barrier protection. A negative pregnancy serum test should be obtained within 7 days of therapy initiation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she must discontinue treatment immediately. Data on fetal outcome and breast-feeding are to be collected for regulatory reporting and drug safety evaluation.. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 6 months after completion abemaciclib plus MK-6482 and at least 3 weeks after the completion of abemaciclib administration.
• Ability to swallow oral medications
• Ability to understand and willingness to sign a written informed consent document.

Exclusion Criteria

A patient will be excluded from the study if he or she meets any of the following criteria:

• Patients receiving any other investigational agents.
• Patients who received prior CDK4/6 inhibitors.
• For Arm 2 only, patients who have received prior HIF-2α inhibitor.
• Participants who have received any continuous or intermittent small molecule therapeutics (excluding monoclonal antibodies) ≤ 4 effective half-lives prior to starting study drug or who have not recovered from side effects of such therapy to grade 1 or less (except for non-clinically significant laboratory abnormalities).
• Patients must have discontinued all biologic therapy including therapeutic antibodies at least 28 days before C1D1.
• Participants who have received wide field radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy to at least grade 1.
• O2 saturation <92% by arterial blood gas analysis or pulse oximetry on room air
• Untreated deep vein thrombosis or pulmonary embolism, or event of deep vein thrombosis or pulmonary embolism within 2 weeks of treatment start. Patient should be on at least 1 week of anticoagulation before C1D1.
• The patient has serious and/or uncontrolled preexisting medical condition(s) that, in the judgment of the investigator, would preclude participation in this study (for example, interstitial lung dis