Inclusion Criteria:
1. Written informed consent obtained from the subject prior to performing any protocol-related procedures, including screening evaluations.
2. Age \>/= 18 years at time of study entry
3. Patients with advanced cancer that is refractory to standard therapy, or that has either relapsed after standard therapy or has no standard therapy that increases survival by at least three months.
4. Patients may have unlimited prior chemotherapy treatments.
5. For dose escalation phase, patients may have evaluable or measurable disease. For ovarian cancer, if no measurable disease is present, patients should have assessable disease such as pleural effusion, ascites, with CA-125 GCIG criteria.
6. For dose expansion phase, patients must have at least one site of measurable disease as defined by RECIST criteria (Version 1.1).
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
8. All prior treatment-related toxicities must be Common Terminology Criteria for Adverse Events (CTCAE) (Version 4.03) \</= Grade 1 at the time of screening (except alopecia).
9. Life expectancy of \>/= 16 weeks.
10. Adequate normal organ and marrow function as defined by: Hemoglobin \>/= 10.0 g/dL with no blood transfusion within 28 days of starting treatment; White blood cells (WBC) \>3 x 10\^9/L; Absolute neutrophil count (ANC) \>/= 1.5 x 10\^9/L (\> 1500 per mm\^3); Platelet count \>/= 100 x 10\^9/L (\>100,000 per mm\^3); Serum bilirubin \</= 1.5 x institutional upper limit of normal (ULN); AST (SGOT) and ALT (SGPT) \</= 2.5 x ULN unless liver metastases are present, in which case it must be \</= 5x ULN; Serum creatinine CL\>50 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance--Creatinine CL (ml/min)=\[Weight(kg)\*(140-Age)\*(0.85 for females or 1 for males)/\[72\*serum creatinine (mg/dL)\].
11. Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
12. Postmenopausal or evidence of non-childbearing status for women of childbearing potential: negative urine or serum pregnancy test within 7 days of study treatment. Postmenopausal is defined as: amenorrheic for 1 year or more following cessation of exogenous hormonal treatments; luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels in the postmenopausal range for women under 50; radiation-induced oophorectomy with last menses \> 1 year ago; chemotherapy-induced menopause with \> 1 year interval since last menses; OR surgical sterilization (bilateral oophorectomy or hysterectomy).
13. Female patients of childbearing potential must use two highly effective forms of contraception.
14. Male patients must use a condom during treatment and for 3 months after the last dose of olaparib when having sexual intercourse with a pregnant woman or with a woman of childbearing potential. Female partners of male patients should also use a highly effective form of contraception if they are of childbearing potential.
15. Additional criteria for escalation cohorts: A) Patients must have RPA (including KRAS, NRAS, NF1, HRAS, and BRAF); B) Prior treatment with MEK inhibitors and/or PARP inhibitors is allowed.
16. Additional criteria for expansion cohorts: A) Patients must have histologically-confirmed advanced or recurrent ovarian cancer with RPA or that had progression during prior PARP inhibitor treatment, endometrial cancer with RPA, or other solid tumor types with RPA; B) Measurable and biopsy-accessible disease; C) Patient must be willing to undergo biopsy procedure; D) Prior treatment with PARP inhibitors is allowed.
Exclusion Criteria:
1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
2. Previous enrollment in the present study.
3. Participation in another clinical study with an investigational product during the 4 weeks prior to therapy initiation.
4. Recent major surgery within 4 weeks prior to starting study treatment. Minor surgery within 2 weeks of starting study treatment. Patients must be recovered from effects of surgery.
5. Patients receiving any systemic chemotherapy or radiotherapy (except for palliative reasons) within 3 weeks prior to study treatment initiation.
6. Concomitant use of known strong (e.g., phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or moderate CYP3A inducers (e.g., bosentan, efavirenz, modafinil). The required washout period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents.
7. 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 required washout period prior to starting olaparib is 2 weeks.
8. Concomitant use of other anti-cancer therapy (chemotherapy, immunotherapy, hormonal therapy (Hormone replacement therapy is acceptable), radiotherapy (except for palliative), biological therapy or other novel agent) or live virus and live bacterial vaccines while the patient is receiving study medication. Strong or Moderate CYP3A inhibitors and inducers should not be taken with study treatment; however, if no other suitable alternative concomitant medication is available, dose reductions may be allowed under careful monitoring.
9. Known severe hypersensitivity to selumetinib or olaparib, their comparators, or combination medications or any excipient of these medicinal products, or history of allergic reactions attributed to compounds of similar chemical or biologic composition to selumetinib or olaparib, or their comparator.
10. History of another primary malignancy except for: A) Malignancy treated with curative intent and with no known active disease \>/= 3 years before the first dose of study drug and of low potential risk for recurrence; B) Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease; C) Adequately treated carcinoma in situ without evidence of disease, e.g. cervical cancer in situ; D) Synchronous endometrial and ovarian cancer is allowed, provided the endometrial cancer is presumed Stage IA/B grade 1/2.
11. Any unresolved toxicity (\>/= CTCAE grade 2) from previous anti-cancer therapy, excluding alopecia.
12. Known or suspected brain metastases or spinal cord compression, unless the condition has been asymptomatic, has been treated with surgery and/or radiation, and has been stable without requiring corticosteroids nor anticonvulsant medications for at least 4 weeks prior to the first dose of study medication. Patients with history of brain metastases should undergo brain imaging within 4 weeks of therapy initiation and at each restaging.
13. Known myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of MDS/AML.
14. Female subjects who are pregnant/breast-feeding or who are of reproductive potential and not employing acceptable methods of birth control.
15. Cardiac conditions as follows: Uncontrolled hypertension (BP \>/= 150/95 mmHg despite medical therapy); Acute coronary syndrome within 6 months prior to starting treatment; Uncontrolled Angina - Canadian Cardiovascular Society grade II-IV despite medical therapy; Symptomatic heart failure NYHA Class II-IV, prior or current cardiomyopathy, or severe valvular heart disease; Prior or current cardiomyopathy including but not limited to the following: known hypertrophic cardiomyopathy or known arrhythmogenic right ventricular cardiomyopathy; Previous moderate or severe impairment of left ventricular systolic function (LVEF \<45% on echocardiography or equivalent on MUGA) even if full recovery has occurred; Severe valvular heart disease;
16. (Continued from previous) Baseline LVEF below the LLN measured by ECHO or institution's LLN for MUGA; Atrial fibrillation with a ventricular rate \>100 bpm on ECG at rest; QTcF \>470ms on two or more timepoints or other factors that increase the risk of QT prolongation such as family history of long QT syndrome.
17. Ophthalmological conditions as follows: Current or past history of retinal pigment epithelial detachment (RPED)/central serous retinopathy (CSR) or retinal vein occlusion; or Intraocular pressure (IOP) \> 21 mmHg or uncontrolled glaucoma (irrespective of IOP)
18. Any evidence of a severe or uncontrolled systemic disease (e.g. unstable or uncompensated respiratory, cardiac, hepatic, or renal disease, active infection (including hepatitis B, hepatitis C, human immunodeficiency virus \[HIV\]), active bleeding diatheses or renal transplant.
19. Previous allogenic bone marrow transplant or double umbilical cord blood transplantation.
20. Whole blood transfusion in the last 120 days prior to entry to the study.
21. Patient is confirmed to have actively symptomatic pneumonitis.
22. Extensive bilateral lung disease on high-resolution computed tomography (HRCT) scan.
23. Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication.
24. Immunocompromised patients, e.g. patients known to be serologically positive for HIV. Patients do NOT need to be tested for HIV in order to enroll on study.
25. Evidence of any other significant clinical disorder or laboratory finding that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results.
26. For the expansion cohorts only: Prior treatment with any MEK inhibitor is not allowed in the expansion cohorts.
