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 disease, severe dyspnea at rest or requiring oxygen therapy, severe renal impairment [e.g. estimated creatinine clearance <30ml/min], history of major surgical resection involving the stomach or small bowel, or preexisting Crohn's disease or ulcerative colitis or a preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea)."
Patient with active systemic bacterial infection (requiring IV antibiotics at the time of initiating study treatment), fungal infection, or detectable viral infection. Patients with known viral infection (such as HIV) are excluded given the potential for interactions between antiretroviral agents and abemaciclib, and the potential for increased risk of lifethreatening infection with therapy that is myelosuppressive. If you are not known to have HIV, a HIV test is required.
Patients with known Hepatitis B or Hepatitis C infection are excluded only if there is evidence of active infection (detectable Hepatitis B surface antigen, detectable Hepatitis C RNA).
Prior allogenic stem cell or solid organ transplant.
Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of oral drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).
Participants who have undergone major surgery ≤ 4 weeks (28 days) prior to starting study drug(s) or who have not recovered from side effects of such therapy.
Participants who are currently taking therapeutic doses of warfarin sodium or any other coumadin-derivative anticoagulant.
Other malignancy diagnosed within 2 years of first study treatment unless negligible risk of metastases or death according to the investigator (included but not limited to carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer, ductal carcinoma in situ of the breast, non-muscle invasive urothelial carcinoma, or other malignancy not deemed to impact patients 5-year life expectancy).
Has a personal history of any of the following conditions: syncope of cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but not limited to, ventricular tachycardia and ventricular fibrillation), sudden cardiac arrest.
Has had any major cardiovascular event within 6 months prior to study drug administration iincluding but not limited to: myocardial infarction, unstable angina, cerebrovascular accident, transient ischemic event or New York Heart Association Class III or IV heart failure. Patients with history of DVT or PE are eligible provided DVT or PE occurred at least 2 weeks prior to C1D1 and anticoagulation has been initiated at least 1 week before C1D1.
History of symptomatic respiratory condition considered clinically significant by the investigator. History of asymptomatic radiation pneumonitis within a previous radiation field is permitted.
Participants with a known hypersensitivity to the study compounds or to its excipients.
Participant is unable or unwilling to abide by the study protocol or cooperate fully with the investigator
Females that are pregnant or lactating
Participants who have taken herbal medications and certain fruits within 7 days prior to starting study drug. Herbal medications include, but are not limited to St. John's wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng. Fruits include the CYP3A inhibitors Seville oranges, grapefruit, pommelos.