Testing the Addition of Abemaciclib to Olaparib for Women With Recurrent Ovarian Cancer

Inclusion Criteria:

• Patients must have histologically confirmed recurrent platinum-resistant epithelialovarian carcinoma (EOC) of any histology, as defined by progression within 6 monthsof the last dose of platinum-based chemotherapy. Both primary platinum resistant andacquired platinum resistant patients are allowed

• High-grade serous histology is required (for the dose expansion cohort only) (dataon BRCA (e.g. germline BRCA, Somatic BRCA, Neither, Unknown) and homologousrecombination deficiency (HRD)/Loss of Heterozygosity (LOH) (e.g. HRD > 42/LOH >16%,HRD score < 42/LOH < 16%, Unknown) is not required for study but will be collectedif available

• Patients must have received 1-3 prior systemic therapies

• Women age >= 18 years. Because no dosing or adverse event data are currentlyavailable on the use of abemaciclib in combination with olaparib in patients <18years of age, children are excluded from this study

• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

• Hemoglobin >= 10 g/dL (within 28 days prior to administration of study treatment)

• Patients may receive erythrocyte transfusions to achieve this hemoglobin levelat the discretion of the investigator. Initial treatment must not begin earlierthan the day after the erythrocyte transfusion

• Absolute neutrophil count >= 1,500/mcL (within 28 days prior to administration ofstudy treatment)

• Platelets >= 100,000/mcL (within 28 days prior to administration of study treatment)

• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (within 28 daysprior to administration of study treatment)

• Patients with Gilbert's syndrome with a total bilirubin =< 2.0 times ULN anddirect bilirubin within normal limits are permitted

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) /alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 3 xinstitutional ULN, unless liver metastases are present in which case they must be =< 5 x ULN (within 28 days prior to administration of study treatment)

• Patients must have creatinine clearance estimated of >= 51 mL/min using theCockcroft-Gault equation or based on a 24-hour urine test (within 28 days prior toadministration of study treatment)

• Glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2 unless data exists supportingsafe use at lower kidney function values, no lower than 30 mL/min/1.73 m^2 (within 28 days prior to administration of study treatment). Estimated GFR calculated usingCockcroft-Gault equation

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviraltherapy with undetectable viral load within 6 months are eligible for this trial

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBVviral load must be undetectable on suppressive therapy, if indicated

• Active hepatitis B virus (HBV) is defined by a known positive HBV surfaceantigen (HBsAg) result. Patients with a past or resolved HBV infection (definedas the presence of hepatitis B core antibody and absence of HBsAg) are eligible

• Patients with a history of hepatitis C virus (HCV) infection must have been treatedand cured. For patients with HCV infection who are currently on treatment, they areeligible if they have an undetectable HCV viral load.

• Patients positive for hepatitis C virus (HCV) antibody are eligible only ifpolymerase chain reaction is negative for HCV ribonucleic acid (RNA)

• Patients with treated brain metastases are eligible if patient is stable for atleast 4 weeks status post (s/p) radiation therapy and off corticosteroids, asascertained by clinical examination and brain imaging (magnetic resonance imaging [MRI] or computed tomography [CT] scan) during the screening period

• Patients with known history or current symptoms of cardiac disease, or history oftreatment with cardiotoxic agents, should have a clinical risk assessment of cardiacfunction using the New York Heart Association Functional Classification. To beeligible for this trial, patients should be class 2B or better

• Postmenopausal or evidence of non-childbearing status, a negative urine or serumpregnancy test within 28 days of study treatment and confirmed prior to treatment onday 1. Postmenopausal is defined as:

• Amenorrheic for 1 year or more following cessation of exogenous hormonaltreatments

• Luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels in thepostmenopausal range for women under 50

• Radiation-induced oophorectomy with last menses > 1 year ago

• Chemotherapy-induced menopause with > 1 year interval since last menses

• Surgical sterilization (bilateral oophorectomy or hysterectomy)

• The effects of abemaciclib and olaparib on the developing human fetus are unknown.For this reason and because CDK-and PARP-inhibiting agents are known to beteratogenic, women of child-bearing potential and their partners, who are sexuallyactive, must agree to the use of one highly effective form of contraception andtheir partner must use a male condom prior to study entry, for the duration of studyparticipation, and for 6 months after the last dose of study treatment. Should awoman become pregnant or suspect she is pregnant while she or her partner isparticipating in this study, she should inform her treating physician immediately

• For the dose expansion cohort, patients must have disease amenable to biopsy forcorrelative studies, specifically at least 1 tumor accessible and safe for biopsy onoffice exam or tumor that a radiologist deems is safe for biopsy in interventionalradiology department based on imaging (dose expansion cohort only). For the doseescalation cohort, patients with evaluable disease are acceptable

• For inclusion in i) the optional genetic research and ii) the optional biomarkerresearch, patients must fulfill the following criteria:

• Provision of informed consent for genetic research prior to collection ofsample

• Provision of informed consent for biomarker research prior to collection ofsample

• If a patient declines to participate in the optional exploratory geneticresearch or the optional biomarker research, there will be no penalty or lossof benefit to the patient. The patient will not be excluded from other aspectsof the study

• Patients may not have received prior CDK 4/6 inhibitors. Previous PARP inhibitor useis allowed in front-line treatment but not for recurrent disease

• Patients who received chemotherapy must have recovered (Common Terminology Criteriafor Adverse Events [CTCAE] grade =< 1) from the acute effects of chemotherapy exceptfor residual alopecia or grade 2 peripheral neuropathy prior to randomization. Awashout period of at least 21 days is required between last chemotherapy dose andrandomization (provided the patient did not receive radiotherapy)

• Patients who received radiotherapy must have completed and fully recovered from theacute effects of radiotherapy. A washout period of at least 28 days is requiredbetween end of radiotherapy and randomization

• For agents other than chemotherapy, a 4 week washout period is required. Previousbevacizumab use is allowed

• Ability to understand and the willingness to sign a written informed consentdocument. Participants with impaired decision-making capacity (IDMC) who have alegally-authorized representative (LAR) and/or family member available will also beeligible

Exclusion Criteria:

• Patients who are receiving any other investigational agents

• History of allergic reaction or hypersensitivity attributed to compounds of similarchemical or biologic composition to abemaciclib, olaparib or any of the excipientsof these products

• Concomitant use of known strong CYP3A inhibitors (e.g. itraconazole, telithromycin,clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir,saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g.ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The requiredwashout period prior to starting study treatment is 2 weeks. Because the lists ofthese agents are constantly changing, it is important to regularly consult afrequently-updated medical reference. As part of the enrollment/informed consentprocedures, the patient will be counseled on the risk of interactions with otheragents, and what to do if new medications need to be prescribed or if the patient isconsidering a new over-the-counter medicine or herbal product

• Patients with psychiatric illness/social situations that would limit compliance withstudy requirements

• Pregnant women are excluded from this study because abemaciclib is a CDK-inhibitingagent and olaparib is a PARP inhibiting agent with the potential for teratogenic orabortifacient effects. Because there is an unknown but potential risk for adverseevents in nursing infants secondary to treatment of the mother with abemaciclib andolaparib, breastfeeding should be discontinued if the mother is treated withabemaciclib and olaparib

• Other malignancy unless curatively treated with no evidence of disease for >= 5years except: adequately treated non-melanoma skin cancer, curatively treated insitu cancer of the cervix, ductal carcinoma in situ (DCIS), stage 1, grade 1endometrial carcinoma

• Resting electrocardiogram (ECG) indicating uncontrolled, potentially reversiblecardiac conditions, as judged by the investigator (e.g., unstable ischemia,uncontrolled symptomatic arrhythmia, congestive heart failure, corrected QT [QTcF]prolongation > 500 ms, electrolyte disturbances, ventricular tachycardia andventricular fibrillation), or sudden cardiac arrest, etc.), or patients withcongenital long QT syndrome

• Patients with myelodysplastic syndrome/acute myeloid leukemia or with featuressuggestive of myelodysplastic syndrome/acute myeloid leukemia (MDS/AML)

• Patients considered a poor medical risk due to a serious, uncontrolled medicaldisorder, non-malignant systemic disease or active, uncontrolled infection that, inthe judgment of the investigator, would preclude participation in this study.Examples include, but are not limited to, uncontrolled ventricular arrhythmia,recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder,unstable spinal cord compression, superior vena cava syndrome, extensiveinterstitial bilateral lung disease on high resolution computed tomography (HRCT)scan, severe dyspnea at rest or requiring oxygen therapy, severe renal impairment [e.g. estimated creatinine clearance < 30 ml/min], history of major surgicalresection involving the stomach or small bowel, or preexisting Crohn's disease orulcerative colitis or a preexisting chronic condition resulting in baseline grade 2or higher diarrhea)

• Patients unable to swallow orally administered medication and patients withgastrointestinal disorders likely to interfere with absorption of the studymedication

• Major surgery within 2 weeks of starting study treatment and patients must haverecovered from any effects of any major surgery

• Previous allogenic bone marrow transplant or double umbilical cord bloodtransplantation (dUCBT)

• Patients with an active systemic fungal infection

• Patients with suspected or history of interstitial lung disease (ILD)/pneumonitis

• Patients with active thromboembolism. Active thromboembolism is defined as adiagnosis of a thromboembolic within the last 6 months or continued evidence ofthromboembolism on imaging despite stable anti-coagulation for 6 months. Patientswith a history of thromboembolism > 6 months ago on anti-coagulation as continuedprevention are eligible