A Study of Alpelisib and Fulvestrant to Treat Endometrial Cancer

Inclusion Criteria:

1. Patient must have advanced (FIGO 2014 Stage III or IV), persistent, or recurrentendometrial carcinoma, which is not likely to be curable by surgery or radiotherapy.Histologic confirmation of recurrent disease is required. For cases of persistentdisease, histologic confirmation of the primary disease with radiologic evidence ofprogression is required.

2. Patients must have endometrioid histology (all grades allowed) based on hysterectomyor biopsy specimen and have positive expression of ER and oncogenic PIK3CA mutationper criteria below. a. PIK3CA mutations considered oncogenic or likely oncogenic. i. Oncogenic/likelyoncogenic PIK3CA mutations identified on tests performed by the labs listed onhttps://ecog-acrin.org/nci-match-eay131-designated-labs will be considered confirmedfor the purposes of this study. ii. Oncogenic/likely oncogenic PIK3CA mutations identified by other tests will needto be confirmed by the study prior to enrollment. b. Estrogen receptor (ER) status will be considered positive if ≥1% of tumor cellsdemonstrate positive nuclear staining by immunohistochemistry. Pathology reportdocumenting ER status must be provided at enrollment. Sites are required to report results of previous MMR and/or MSI status testing inthe EDC if available.

3. All patients must have measurable disease. Measurable disease is defined by RECISTversion 1.1. Measurable disease is defined as at least one lesion that can beaccurately measured in at least one dimension (longest diameter to be recorded).Each lesion must be greater than or equal to 10mm when measured by CT, MRI orcaliper measurement by clinical exam; or greater than or equal to 20mm when measuredby chest x-ray. Lymph nodes must be greater than or equal to 15mm in short axis whenmeasured by CT or MRI. Patients must have at least one "target lesion" to be used to assess response onthis protocol as defined by RECIST 1.1. Tumors within a previously irradiated fieldwill be designated as "non-target" lesions unless progression is documented or abiopsy is obtained to confirm persistence at least 90 days following completion ofradiation therapy.

4. Prior chemotherapy in the adjuvant setting for Stage I, II, or III ormetastatic/recurrent/Stage IV is permitted. Prior chemoradiotherapy for a pelvicrecurrence is permitted. Prior immunotherapy and/or targeted therapy is allowed in addition to, incombination with, in lieu of, or subsequent to prior chemotherapy. Prior hormone therapy (progesterone, tamoxifen, aromatase inhibitor) is allowed andnot considered a prior line of therapy. Prior treatment with fulvestrant notallowed. There are no limits on the number of prior lines of chemotherapy. Patients whoreceived prior chemotherapy must have recovered (Common Terminology Criteria forAdverse Events [CTCAE] Grade less than or equal to 1) from the acute effects ofchemotherapy except for residual alopecia or Grade 2 peripheral neuropathy prior toenrollment. A washout period of at least 21 days is required between lastchemotherapy dose and initiation of therapy. Patients who received radiotherapy must have completed and fully recovered from theacute effects of radiotherapy. A washout period of at least 14 days is requiredbetween end of radiotherapy and initiation of therapy.

5. Patient must be able to swallow oral medications.

6. Patient must have an ECOG performance status of 0 to 2.

7. Patients must have adequate glucose control as defined by the following (bothcriteria must be met):

• Fasting blood glucose (FBG) ≤140/dL (7.7mmol/L) AND

• Hemoglobin A1c (HbA1c) ≤6.4%

8. Patients must have adequate organ and marrow function as defined below NOTE:Institutional/laboratory upper limit of normal = ULN Institutional/laboratory lowerlimit of normal = LLN Bone marrow function:

• Absolute neutrophil count (ANC) greater than or equal to 1000/mcl

• Platelets greater than or equal to 100,000 cells/mcl

• Hemoglobin greater than or equal to 8 g/dL (Patients may receive erythrocytetransfusions to achieve this hemoglobin level at the discretion of theinvestigator. Initial treatment must not begin earlier than the day aftererythrocyte transfusion). Renal function:

• Creatinine Clearance ≥ 35 mL/min using Cockcroft-Gault formula Pancreatic function:

• Fasting Serum amylase ≤ 2 × ULN

• Fasting Serum lipase ≤ ULN Hepatic function:

• Bilirubin less than or equal to 1.5 x ULN (Patients with Gilbert's syndromewith a total bilirubin ≤2 times ULN and direct bilirubin within normal limitsare permitted).

• ALT (alanine aminotransferase) and AST (aspartate aminotransferase) less thanor equal to 3 x ULN

• Albumin greater than or equal to 2.8 g/dL

9. Patients must have signed an approved informed consent and authorization permittingrelease of personal health information.

10. Patients must be at least 18 years of age.

11. Patients of childbearing potential must have a negative serum pregnancy test priorto the study entry and be practicing a highly effective form of contraception duringthe study treatment and for 8 weeks after stopping the treatment.

Highly effective contraception methods include combination of any of the following (NOTE: Estrogen containing contraceptives are prohibited):

• Use of oral, injected, or implanted hormonal contraceptives or;

• Placement of an intrauterine device (IUD) or intrauterine system (IUS);

• Barrier methods of contraception: condom or occlusive cap (diaphragm orcervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository;

• Total abstinence or;

• Male/female sterilization. Women are considered post-menopausal and not ofchild-bearing potential if they have had 12 months of natural (spontaneous)amenorrhea with an appropriate clinical profile (e.g., age appropriate, history ofvasomotor symptoms) or have had surgical bilateral oophorectomy (with or withouthysterectomy) or tubal ligation at least six weeks prior to registration. In thecase of oophorectomy alone, only when the reproductive status of the woman has beenconfirmed by follow up hormone level assessment is she considered not ofchild-bearing potential.

Exclusion Criteria:

1. Patients who have previously received fulvestrant or any PIK3CA, PI3K, mTOR, or AKTinhibitor.

2. Patients with clear cell, serous, carcinosarcoma, mixed histology endometrialcancers, or uterine sarcomas.

3. Patients with known intolerance or hypersensitivity to alpelisib or fulvestrant, orany of their excipients.

4. Patient has had major surgery within 14 days prior to study treatment start and/orhas not recovered from major side effects.

5. Patients with an established diagnosis of diabetes mellitus type I or uncontrolledtype II (based on fasting blood glucose [FBG] and HemoglobinA1c [HbA1c], seeinclusion criterion 67).

6. Patients with history of osteonecrosis of the jaw.

7. Patients with concomitant invasive malignancy or a history of other invasivemalignancies, with the exception of non-melanoma skin cancer, are excluded if thereis any evidence of other malignancy being present within the past five years.Patients are also excluded if their previous cancer treatment contraindicates thisprotocol.

8. Patients with active bacterial infection (requiring intravenous [IV] antibiotics attime of initiating study treatment, fungal infection, or detectable viral infection (such as known human immunodeficiency virus (HIV) positivity or with known activehepatitis B or C [for example, hepatitis B surface antigen positive]). Screening isnot required for enrollment.

9. Patients with a serious pre-existing medical condition(s) that would precludeparticipation in this study (for example: interstitial lung disease or pneumonitis,severe dyspnea at rest or requiring oxygen therapy, severe renal impairment (i.e.estimated creatinine clearance <30ml/min), history of major surgical resectioninvolving the stomach or small bowel, or preexisting Crohn's disease or ulcerativecolitis or pre-existing chronic condition resulting in baseline grade 2 or higherdiarrhea).

10. Patients with a known history of cardiac disease. This includes:

• Uncontrolled hypertension, defined as systolic greater than 150mm Hg ordiastolic greater than 90mm Hg despite antihypertensive medications

• Myocardial infarction, unstable angina, symptomatic pericarditis, or coronaryartery bypass graft (CABG) within 6 months prior to registration.

• New York Heart Association (NYHA) Class II or greater congestive heart failure.

• History of clinically significant cardiac arrhythmias (i.e. ventriculartachycardia or ventricular fibrillation, complete left bundle branch block,high grade AV block (e.g. bifascicular block, Mobitz type II and third degreeAV block without pacemaker in place) or serious cardiac arrhythmia requiringmedication. This does not include asymptomatic atrial fibrillation withcontrolled ventricular rate.

• Long QT syndrome, family history of idiopathic sudden death or congenital longQT syndrome, or Fridericia QT correction formula (QTcF) > 470 msec atscreening.

• Cerebrovascular accident (CVA, stroke), transient ischemic attack (TIA) within 6 months prior to the first date of study therapy.

• Syncope of cardiovascular etiology,

• Sudden cardiac arrest.

11. Patient is currently receiving any of the following medications and cannot bediscontinued 7 days prior to the start of the treatment:

• Strong CYP3A4 inducers

• Inhibitors of BCRP.

12. Patients who are pregnant or breast-feeding.

13. Patients with known central nervous system metastases which was not previouslytreated and not fulfilling the following 3 criteria to be eligible for the study:

• Completed prior therapy (including radiation and/or surgery) for CNS metastases ≥ 28 days prior to the start of study entry and

• CNS tumor is clinically stable at the time of screening and

• Participant is not receiving steroids and/or enzyme inducing anti-epilepticmedications for brain metastases.

14. Patients with an impairment of gastrointestinal function or gastrointestinal diseasethat may significantly alter the absorption of the study drugs (i.e. ulcerativedisease; uncontrolled nausea, vomiting and/or diarrhea; malabsorption syndrome;clinical signs and symptoms of gastrointestinal obstruction; and/or patients whorequire parenteral hydration and/or nutrition).

15. Patients who plan to receive live attenuated vaccines within 1 week of start ofalpelisib and during the study. Patients should also avoid close contact with otherswho have received live attenuated vaccines. Examples of live attenuated vaccinesinclude intranasal influenza, measles, mumps, rubella, oral polio, BCG< yellowfever, varicella, and TY21a typhoid vaccines.

16. Patients with active bleeding or pathologic conditions that carry high risk ofbleeding such as known bleeding disorder or coagulopathy.

17. Patients who are currently part of or have participated in any clinicalinvestigation with an investigational drug within 30 days prior to dosing, or within 5 half-lives of the investigational product, whichever is longer.

18. Patient is not able to understand and to comply with study instructions andrequirements, including oral administration of study treatment