Gedatolisib Plus Fulvestrant With or Without Palbociclib vs Standard-of-Care for the Treatment of Patients With Advanced or Metastatic HR+/HER2- Breast Cancer

Inclusion Criteria:

1. Histologically or cytologically confirmed diagnosis of metastatic or locally advancedbreast cancer Adult females, pre- and/or post-menopausal, and adult males.Pre-menopausal (and peri-menopausal) women can be enrolled if amenable to treatmentwith an LHRH agonist. Patients are to have commenced concomitant treatment with LHRHagonist prior to or on Cycle 1, Day 1 and must be willing to continue on it for theduration of the study.
2. Negative pregnancy test for women who are not surgically sterile. Female subjects whoare not surgically sterile must use a medically-effective contraceptive method fromscreening until 1 year after the last dose of study treatment
3. Confirmed diagnosis of estrogen receptor positive and/or progesterone receptorpositive, as per American Society of Clinical Oncology/College of AmericanPathologists (ASCO-CAP) guidelines (2020), based on most recent tumor biopsy utilizingan assay consistent with local standards
4. Documented HER2 immunohistochemistry (IHC) negative as per ASCO-CAP 2018 guidance
5. Adequate archival or fresh tumor tissue for the analysis of PIK3CA mutational status
6. Subject has radiologically evaluable disease (measurable and/or non-measurable)according to RECIST v1.1, per local assessment. Mixed lytic/blastic or lytic lesionswith measurable soft tissue component are allowed.
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
8. Life expectancy of at least 3 months
9. Progressed during or after CDK4/6 inhibitor combination treatment with non-steroidalaromatase inhibitor (AI)
10. Adequate bone marrow, hepatic, renal and coagulation function

Exclusion Criteria:

1. History of malignancies other than adequately treated non-melanoma skin cancer,curatively treated in situ cancer of the cervix, or other solid tumors curativelytreated with no evidence of disease for ≥3 years
2. Prior treatment with a phosphoinositide 3-kinase (PI3K) inhibitor, a protein kinase B (Akt) inhibitor, or a mechanistic target of rapamycin (mTOR) inhibitor
3. More than one prior treatment with chemotherapy for advanced disease (prior adjuvantor neoadjuvant chemotherapy is permitted)
4. More than 2 lines of prior endocrine therapy treatment
5. Bone only disease that is only blastic with no soft tissue component
6. Subjects with type 1 diabetes or uncontrolled type 2 diabetes
7. Known and untreated, or active, brain or leptomeningeal metastases a. Subjects with previously treated central nervous system (CNS) metastases may beenrolled in the study if they meet the following criteria: do not require supportivetherapy with steroids; do not have seizures and do not exhibit uncontrolledneurological symptoms; stable disease confirmed by radiographic assessment within atleast 4 weeks prior to enrollment
8. Patients with advanced, symptomatic, visceral spread that are at risk oflife-threatening complication in the short-term
9. History of clinically significant cardiovascular abnormalities such as: Congestiveheart failure (New York Heart Association (NYHA) classification ≥ II within 6 monthsof study entry
10. Myocardial infarction within 12 months of study entry
11. History of any cardiac arrhythmias, (e.g., ventricular tachycardia), completeleft bundle branch block, high grade AV block (e.g., bifascicular block, Mobitztype II and third degree AV block), supraventricular, nodal arrhythmias, orconduction abnormality in the previous 12 months
12. Uncontrolled hypertension defined by systolic blood pressure (SBP) ≥160 mmHgand/or diastolic blood pressure (DBP) ≥100 mmHg, with or without antihypertensivemedication (initiation or adjustment of antihypertensive medication[s] is allowedprior to screening)
13. Long QT syndrome, family history of idiopathic sudden death or congenital long QTsyndrome, or any of the following:

• i. Risk factors for Torsades de Pointes (TdP) including uncorrectedhypokalemia or hypomagnesemia, history of cardiac failure, or history ofclinically significant/symptomatic bradycardia
• ii. Concomitant medication(s) with a known risk to prolong the QT intervaland/or known to cause TdP that cannot be discontinued or replaced by safealternative medication
• iii. Bradycardia (heart rate <50 beats per minute at rest) byelectrocardiogram (ECG) or pulse
• iv. On screening, inability to determine the corrected QT interval usingFridericia's formula (QTcF) on the ECG (i.e., unreadable or notinterpretable) or QTcF >450 msec for males and >460 msec for females (determined by mean of triplicate ECGs at screening)

10. Known hypersensitivity to the study drugs or their components
11. Pregnant or breast-feeding women
12. Concurrent participation in another clinical trial
13. Subjects must agree not to participate in another clinical trial at any timeduring participation in VIKTORIA-1.