Testing the Use of the Combination of Selumetinib and Olaparib or Selumetinib Alone Targeted Treatment for RAS Pathway Mutant Recurrent or Persistent Ovarian and Endometrial Cancers, A ComboMATCH Treatment Trial

Inclusion Criteria:

• Patient must have enrolled onto EAY191 and must have been given a treatmentassignment to ComboMATCH to EAY191-N4 based on the presence of an actionablemutation as defined in EAY191

• Patients must be enrolled on the ComboMATCH Master Registration Trial EAY191

• Patients must have RAS pathway mutations as determined by the ComboMATCH screeningassessment

• Cohort 1: Patients with histologically confirmed RAS pathway mutant ovarian,primary peritoneal, or fallopian tube ("ovarian") cancer (activating mutationsin KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, or inactivating mutations in NF1)

• Cohort 2: Patients with histologically confirmed RAS pathway mutant endometrialcancer (activating mutations in KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, orinactivating mutations in NF1).

• Patients must have disease that can be safely biopsied and agree to a pre-treatmentbiopsy, if disease cannot be safely biopsied, or have archival tissue available fromwithin 12 months prior to registration on the ComboMATCH Registration Trial (EAY191)

• Patients must have progressed after first-line treatment for recurrent or persistentdisease

• Patients with ovarian cancer should not be eligible for further platinum-basedtherapy

• Patients with endometrial cancer must have received or been offered an immuneoncology agent (alone or in combination with lenvatinib) unless there are existingcontraindications for immune oncology agents or lenvatinib

• Patients may have received unlimited prior therapy

• Patients must have measurable and biopsiable disease. Measurable disease is definedby RECIST 1.1 as at least one lesion that can be accurately measured in at least onedimension (longest diameter to be recorded). Each lesion must be > 10 mm whenmeasured by CT, magnetic resonance imaging (MRI) or caliper measurement by clinicalexam; or > 20 mm when measured by chest x-ray. Lymph nodes must be > 15 mm in shortaxis when measured by CT or MRI

• Patients must have at least one "target lesion" separate from the lesion to bebiopsied to be used to assess response on this protocol as defined by RECISTversion 1.1. Tumors within a previously irradiated field will be designated as "non-target" lesions unless progression is documented or a biopsy is obtainedto confirm persistence at least 90 days following completion of radiationtherapy

• Prior therapy must have been completed at least four weeks prior to registration

• Age >= 18

• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1 or 2

• Hemoglobin (Hgb) >= 9.5 g/dL with no blood transfusion in the past 28 days (within 14 days prior to registration)

• Platelets >= 100,000/mcl (within 14 days prior to registration)

• Absolute neutrophil count (ANC) >= 1,500/mcl (within 14 days prior to registration)

• Patients must have creatinine clearance estimated of >= 50 mL/min using theCockcroft-Gault equation or based on a 24 hour urine test (within 14 days prior toregistration)

• Total bilirubin level =< 1.5 x institutional upper limit of normal (ULN) or =< 3 xULN in the presence of documented Gilbert's syndrome (unconjugatedhyperbilirubinemia) (within 14 days prior to registration)

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x ULN (within 14 days prior to registration)

• Patients must be able to swallow and retain oral medications and be withoutgastrointestinal illnesses that would preclude absorption of selumetinib or olaparib

• 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

• Women of childbearing potential (WOCBP) must agree to use two forms of birth control (hormonal or barrier method of birth control; abstinence) during the study and for 12 weeks after completing treatment

• Non-sterilized male partners of WOCBP (including males sterilized by a methodother than bilateral orchidectomy e.g., vasectomy) who intend to be sexuallyactive with a female partner must be using an acceptable method ofcontraception such as male condom plus spermicide (condom alone in countrieswhere spermicides are not approved) from the time of screening throughout thetotal duration of the study and the drug washout period (at least 16 weeksafter the last dose of study intervention) to prevent pregnancy in a partner.Periodic abstinence, the rhythm method, and the withdrawal method are notacceptable methods of contraception. Vasectomized (i.e., sterile) males areconsidered fertile and should still use a male condom plus spermicide asindicated above during the clinical study

• Patients with a prior or concurrent malignancy whose natural history or treatmentdoes not have the potential to interfere with the safety or efficacy assessment ofthe investigational regimen are eligible for this trial

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

• Patients with evidence of chronic hepatitis B virus (HBV) infection must have anundetectable HBV viral load on suppressive therapy, if indicated

• Patients with a history of hepatitis C virus (HCV) infection must have beentreated and cured. For patients with HCV infection who are currently ontreatment, they are eligible if they have an undetectable HCV viral load

• Patients with new or progressive brain metastases (active brain metastases) orleptomeningeal disease are eligible if the treating physician determines thatimmediate central nervous system (CNS) specific treatment is not required and isunlikely to be required during the first cycle of therapy

• Patients with treated brain metastases are eligible if follow-up brain imagingafter CNS-directed therapy shows no evidence of progression

• Extra caution should be taken with olaparib, as it crosses the blood brainbarrier and can cause edema in brain metastases

• The patient or a legally authorized representative must provide study-specificinformed consent prior to study entry and, for patients treated in the United States (U.S.), authorization permitting release of personal health information

Exclusion Criteria:

• Patients who have received any MEK inhibitors

• Patients who have progressed while receiving a PARP inhibitor

• Patients who have received chemotherapy or radiotherapy within 4 weeks (6 weeks fornitrosoureas or mitomycin C) prior to registration

• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia

• Patients with uncontrolled intercurrent illness

• Patients with >= grade 2 neuropathy within 14 days of registration

• Patients with severe (Child-Pugh C) liver dysfunction

• Patients with a history of allergic reactions attributed to compounds of similarchemical or biologic composition to olaparib and selumetinib or any excipientsthereof

• Concomitant use of known strong (e.g., phenobarbital, enzalutamide, phenytoin,rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) ormoderate CYP3A inducers (e.g., bosentan, efavirenz, modafinil). The required washoutperiod prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3weeks for other agents

• Supplementation with vitamin E greater than 100% of the daily recommended dose.Any multivitamin containing vitamin E must be stopped prior to study enrollmenteven if less than 100% of the daily recommended dosing for vitamin E

• Vitamin E must not be taken in the 7 days prior to initiation of treatment withselumetinib

• 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 known moderate CYP3A inhibitors (e.g. ciprofloxacin, erythromycin, diltiazem, Fluconazole, verapamil). The requiredwashout period prior to starting olaparib is at least 14 days or 5 half-lives (whichever is longer) before the first dose of study medication

• Concomitant use of strong CYP2C19 inhibitors (e.g., ticlopidine) or moderate CYP2C19inhibitors (e.g., omeprazole). The required washout period prior to startingselumetinib is at least 14 days or 5 half-lives (whichever is longer) before thefirst dose of study medication

• Have received or are receiving an investigational medicinal product (IMP) or othersystemic anti-cancer treatment (including chemotherapy, immunotherapy, targetedtherapy, biologic therapy, tumor embolization, or monoclonal antibodies) within 4weeks prior to registration, or within a period during which the IMP or systemictarget treatment has not been cleared from the body (e.g., a period of 5 'half-lives'), whichever is longer

• Known myelodysplastic syndrome/acute myeloid leukemia or with features suggestive ofmyelodysplastic syndrome (MDS)/acute myeloid leukemia (AML)

• Patients who have had previous organ transplant, allogenic bone marrow transplant ordouble umbilical cord blood transplantation

• Patients who have had whole blood transfusion within 28 days prior to registration

• Patients with ophthalmological conditions as follows:

• Current or past history of retinal pigment epithelial detachment/central serousretinopathy or retinal vein occlusion.

• Intraocular pressure >21 mmHg (or ULN adjusted by age) or uncontrolled glaucoma (irrespective of intraocular pressure [IOP]). Subjects with known glaucoma andincreased IOP who do not have meaningful vision (light perception only or nolight perception) and are not experiencing pain related to the glaucoma, may beeligible after discussion with the study chair

• Patients with any other significant abnormality on ophthalmic examinationshould be discussed with the study chair for potential eligibility

• Ophthalmological findings secondary to long-standing optic pathway glioma (suchas visual loss, optic nerve pallor or strabismus) or longstandingorbito-temporal plexiform neurofibroma (PN) (such as visual loss, strabismus)will NOT be considered a significant abnormality for the purposes of the study

• Patients with severe, active co-morbidity defined as any of the following:

• History and/or confirmed pneumonitis

• Uncontrolled hypertension (blood pressure [BP] >= 150/90 mmHg despite medicaltherapy)

• Acute coronary syndrome within 6 months prior to registration

• Uncontrolled atrial fibrillation

• Known family history of long QT syndrome

• Women who are pregnant or unwilling to discontinue nursing