A Randomized Trial of Selumetinib and Olaparib or Selumetinib Alone in Patients with Recurrent or Persistent RAS Pathway Mutant Ovarian and Endometrial Cancers

Protocol: ECOG – EAY191-N4

SCHEMA EAY191-E4

Please Note: Below is a partial list of eligibility, please contact the Genesys Hurley Cancer Institute, Research Department at (810)762-8181, (810)762-8079 or (810)762-8038 to discuss the complete eligibility requirements.  Thank you!

Eligibility:

1. Patients must be enrolled on the ComboMATCH Master Registration Trial EAY191
2. Patients must have RAS pathway mutations as determined by the ComboMATCH screening assessment.  Cohort 1: Patients with histologically confirmed RAS pathway mutant ovarian, primary peritoneal, or fallopian tube (“ovarian”) cancer (activating mutations in KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, or inactivating mutations in NF1).  Cohort 2: Patients with histologically confirmed RAS pathway mutant endometrial cancer (activating mutations in KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, or inactivating mutations in NF1).
3. Patients must have disease that can be safely biopsied and agree to a pre-treatment biopsy or, if disease cannot be safely biopsied, have archival tissue available from within 12 months prior to the date of registration on the ComboMATCH Registration Trial (EAY191).
4. Patients must have progressed after first-line treatment for recurrent or persistent disease.
5. Patients with ovarian cancer should not be eligible for further platinum-based therapy.
6. Patients with endometrial cancer must have received or been offered an immune oncology agent (alone or in combination with lenvatinib) unless there are existing contraindications
   for immune oncology agents or lenvatinib.
7. Patients may have received unlimited prior therapy.
8. Patients must have measurable and biopsiable disease.
9. Prior therapy must have been completed at least four weeks prior to registration.
10. Age ≥ 18.
11. ECOG Performance Status of 0, 1 or 2.
12. Patients must be able to swallow and retain oral medications and be without gastrointestinal illnesses that would preclude absorption of selumetinib or olaparib.
13. Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the
    New York Heart Association Functional Classification.
14. Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational
    regimen are eligible for this trial.
15. HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of registration are eligible for this trial.
16. Patients with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible if the treating physician determines that immediate CNS
    specific treatment is not required and is unlikely to be required during the first cycle of therapy.
17. Patients with treated brain metastases are eligible if follow-up brain imaging after CNSdirected therapy shows no evidence of progression.

Ineligibility:

1. Patients who have received any MEK inhibitors.
2. Patients who have progressed while receiving a PARP inhibitor.
3. Patients who have received chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to registration.
4. Patients with uncontrolled intercurrent illness.
5. 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.
6. 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 required washout period prior to
   starting olaparib is at least 14 days or 5 half-lives (whichever is longer) before the first dose of study medication.
7. Concomitant use ofstrong CYP2C19 inhibitors (e.g., ticlopidine) or moderate CYP2C19 inhibitors (e.g., omeprazole). The required washout period prior to starting selumetinib is at
   least 14 days or 5 half-lives (whichever is longer) before the first dose of study medication.
8. Have received or are receiving an investigational medicinal product (IMP) or other systemic anti-cancer treatment (including chemotherapy, immunotherapy, targeted therapy, biologic
   therapy, tumor embolization, or monoclonal antibodies) within 4 weeks prior to registration, or within a period during which the IMP or systemic target treatment has not been cleared
   from the body (e.g., a period of 5 ‘half-lives’), whichever is longer.
9. Known myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of MDS/AML.
10. Patients who have had previous organ transplant, allogenic bone marrow transplant or double umbilical cord blood transplantation.
11. Patients who have had whole blood transfusion within 28 days prior to registration.
12. Patients with severe, active co-morbidity.
13. Patients with ophthalmological conditions.