Phase Ib Study of AlpeliSib With PEmbroLizumab in Patients With mEtastatic Breast caNcer or melanomA (SELENA)

Inclusion Criteria:

1. Patients must be 18 years or older.

2. Patients must be willing and able to provide informed consent.

3. In the dose escalation, patients must have histologically documented locallyadvanced, unresectable, or metastatic melanoma or TNBC that has progressed ontreatments that are known to prolong survival or for which no standard treatment isavailable or refused such therapy. Presence of active brain metastases is notrequired. Patients with active metastases as defined below can be eligible in thedose escalation.

4. In the dose expansion, patients must have histologically documented locallyadvanced, unresectable, or metastatic melanoma or TNBC that has progressed ontreatments that are known to prolong survival or for which no standard treatment isavailable or refused such therapy.

5. Melanoma patients without brain metastases who have progressed on an anti-PD-1or anti-PD-L1-based regimen.

6. Melanoma patients with active and untreated brain metastases who haveprogressed on an anti-PD-1 or anti-PD-L1-based regimen.

7. TNBC patients (defined as ER <1%, HER2 0, 1+, 2+, and fluorescence in situhybridization negative) with active untreated brain metastases. Prior treatmentwith anti-PD-1/anti-PD-L1 is not required.

8. All patients must have had a brain magnetic resonance imaging (MRI) scan in theprevious 28 days to confirm eligibility for the following cohorts:

9. Dose escalation and dose expansion Cohort 1: Confirmed absence of untreatedbrain metastases in patients with histologically confirmed advanced melanoma.Prior surgery for brain metastases must have been completed at least 4 weeksprior study treatment initiation, whole brain radiation therapy must have beencompleted at least 3 weeks prior to study treatment initiation, andstereotactic radiosurgery must have been completed within 7 days prior to studytreatment initiation.

10. Dose escalation and dose expansion Cohorts 2 and 3: At least one confirmedmeasurable untreated brain lesion ≥ 0.5 cm and < 3.0 cm in the longest axis.

11. Has measurable disease based on the RECIST v1.1.

12. Has adequate organ function as defined in Table 2:

13. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (Appendix 4).

14. Has a life expectancy of at least 12 weeks.

15. Able to swallow and retain orally administered medication.

16. In the dose expansion, patients with EC disease must be willing to provide tissuefrom a newly obtained, safely accessible core or excisional biopsy lesion atpre-treatment and at least one time point while on study treatment. Correlativebiopsies will be optional in the dose escalation portion of the study. Newlyobtained biopsy is defined as a specimen obtained up to 6 weeks (42 days) prior toinitiation of study treatment on Day 1 without intervening systemic therapy.

17. Women of childbearing potential (WOCBP) should have a negative urine pregnancy testwithin 72 hours prior to receiving the first dose of study treatment. If the urinetest is positive or cannot be confirmed as negative, a serum pregnancy test will berequired.

18. Alpelisib and pembrolizumab can cause fetal harm when administered to a pregnantwoman. Therefore, WOCBP must agree to use adequate contraception (hormonal orbarrier method of birth control; abstinence) from the time of screening through 4months after the last dose of study treatment. Refer to Pregnancy Assessment PolicyMD Anderson Cancer Center (MDACC) Institutional Policy # CLN1114. This includes allfemale patients between the onset of menses and 55 years unless the patient presentswith an applicable exclusionary factor such as one of the following:

19. Postmenopausal (no menses in ≥ 12 consecutive months)

20. History of hysterectomy or bilateral salpingo-oophorectomy

21. Ovarian failure (follicle-stimulating hormone and estradiol in menopausal rangeand have received whole pelvic radiation therapy)

22. History of bilateral tubal ligation or another surgical sterilization procedure

23. Approved methods of birth control are as follows: hormonal contraception (i.e.,birth control pills, injection, implant, transdermal patch, vaginal ring),intrauterine device, tubal ligation or hysterectomy, patient/partner post vasectomy,implantable or injectable contraceptives, and condoms plus spermicide. Not engagingin sexual activity for the total duration of the study and the study treatmentwashout period is an acceptable practice; however, periodic abstinence, the rhythmmethod, and the withdrawal method are not acceptable methods of birth control.Should a woman become pregnant or suspect she is pregnant while she or her partneris participating in this study, she should inform her treating physicianimmediately.

24. Male patients with partner(s) of childbearing potential must agree to use adequatecontraception from the time of screening through 4 months after the last dose ofstudy treatment.

Exclusion Criteria:

1. Has a history of or active autoimmune disease, as follows: history of inflammatorybowel disease, history of symptomatic disease (e.g., rheumatoid arthritis, systemicprogressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmunevasculitis [e.g., Wegener's granulomatosis]), motor neuropathy considered ofautoimmune origin (e.g., Guillain-Barré syndrome and myasthenia gravis), or historyof autoimmune thyroiditis (patients may be eligible if their current thyroiddisorder is treated and stable with replacement or other medical therapy).

2. Has active infection or had a serious general medical condition(s) (such as vascularaccident) in the past 6 months.

3. Any unresolved > Grade 1 toxicity (per CTCAE v5.0) from previous anticancer therapyor previously administered agent at the time of enrollment, except for alopecia andGrade 2 anemia (if hemoglobin is > 9 g/dL). Note: If the patient received majorsurgery, he/she must have recovered adequately from the toxicity and/orcomplications from the intervention prior to starting study treatment.

4. Patients who received chemotherapy or radiotherapy within 2 weeks (6 weeks fornitrosoureas or mitomycin C) prior to starting study treatment.

5. Presence of any clinically significant gastrointestinal abnormality or othercondition(s) (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea,malabsorption syndrome, or small bowel resection) that may alter absorption such asmalabsorption syndrome or major resection of the stomach or substantial portion ofthe small intestine based on investigator discretion.

6. Previous major surgery within 14 days prior to enrollment.

7. Evidence of severe or uncontrolled systemic disease (e.g., unstable or uncompensatedrespiratory, hepatic, renal, or cardiac disease).

8. Established diagnosis of diabetes mellitus type I or uncontrolled type II (based onfasting blood glucose and HbA1c [see inclusion criteria #4]).

9. History of acute pancreatitis within 1 year of screening or past medical history ofchronic pancreatitis.

10. History of severe cutaneous reaction, such as SJS, erythema multiforme (EM), TEN, ordrug reaction with eosinophilia and systemic symptoms (DRESS).

11. Based on average of triplicate 12-lead electrocardiogram (ECG), a mean resting QTcinterval using Fridericia formula > 450 msec for males and > 470 msec for females atscreening or a history of congenital long QT syndrome or QTc > 480 msec for patientswith a bundle branch block.

12. History or evidence of cardiovascular risk including any of the following:

13. History of myocardial infarction, acute coronary syndromes (including unstableangina), coronary angioplasty, stenting, or bypass grafting within 6 monthsprior to enrollment.

14. Class III or IV heart failure as defined by the New York Heart Associationfunctional classification system.

15. Known left ventricular ejection fraction < 50%.

16. Known cardiac metastases.

17. Poorly controlled hypertension (defined as systolic blood pressure ≥150 mmHg ordiastolic blood pressure >100 mmHg based on a mean of three measurements taken atapproximately 2-minute intervals). Note: Initiation or adjustment of antihypertensive medication(s) is permitted ifdone 30 or more days prior to enrollment.

18. For dose expansion Cohorts 2 and 3 with active brain metastases:

19. Patients must not have any of the following on the screening brain MRI:

• Any untreated brain lesions > 3.0 cm in size.
• Any brain lesion thought to require immediate local therapy, including (but not limited to) a lesion in an anatomic site where increase in sizeor possible treatment-related edema may pose risk to the patient (e.g.,brainstem lesions). Patients who undergo local treatment for such lesionsmay still be eligible for the study.

2. Ongoing use of systemic corticosteroids for control of symptoms of brainmetastases at a total daily dose of dexamethasone (or equivalent) > 4 mg.

• Poorly controlled (> 1/week) generalized or complex partial seizures, ormanifestation of neurologic progression due to brain metastasesnotwithstanding CNS-directed therapy.

15. Has a history of (non-infectious) pneumonitis that required steroids or currentpneumonitis.

16. Has a history or current evidence of any condition, therapy, or laboratoryabnormality that might confound the results of the trial, interfere with thepatient's participation for the full duration of the trial, or is not in the bestinterest of the patient to participate, in the opinion of the treating investigator.

17. Has known psychiatric or substance abuse disorder that in the opinion of thetreating physician or principal investigator (PI) would interfere with cooperationwith the requirements of the trial.

18. Known history of hepatitis B or C or positive test for human immunodeficiency virus.

19. Has received a live vaccine within 30 days of planned start of study treatment. Note: Seasonal influenza vaccines for injection are generally inactivated fluvaccines and are allowed; COVID-19 vaccines are allowed; however intranasalinfluenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are notallowed.

20. Current use of or anticipated requirement during the study of any prohibitedmedication(s) (See Section 5.5.2).

21. History of allergic reactions attributed to compounds of similar chemical orbiologic composition to alpelisib and pembrolizumab.

22. Pregnant or nursing.